非吸烟女性原发性肺癌的风险因素

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The etiology of lung cancer in never‐smokers remains elusive, despite 15% of lung cancer cases in men and 53% in women worldwide being unrelated to smoking. Here, we aimed to enhance our understanding of lung cancer pathogenesis among never‐smokers using untargeted metabolomics. This nested case‐control study included 395 never‐smoking women who developed lung cancer and 395 matched never‐smoking cancer‐free women from the prospective Shanghai Women's Health Study with 15,353 metabolic features quantified in pre‐diagnostic plasma using liquid chromatography high‐resolution mass spectrometry. Recognizing that metabolites often correlate and seldom act independently in biological processes, we utilized a weighted correlation network analysis to agnostically construct 28 network modules of correlated metabolites. Using conditional logistic regression models, we assessed the associations for both metabolic network modules and individual metabolic features with lung cancer, accounting for multiple testing using a false discovery rate (FDR) < 0.20. We identified a network module of 121 features inversely associated with all lung cancer (p = .001, FDR = 0.028) and lung adenocarcinoma (p = .002, FDR = 0.056), where lyso‐glycerophospholipids played a key role driving these associations. Another module of 440 features was inversely associated with lung adenocarcinoma (p = .014, FDR = 0.196). Individual metabolites within these network modules were enriched in biological pathways linked to oxidative stress, and energy metabolism. These pathways have been implicated in previous metabolomics studies involving populations exposed to known lung cancer risk factors such as traffic‐related air pollution and polycyclic aromatic hydrocarbons. Our results suggest that untargeted plasma metabolomics could provide novel insights into the etiology and risk factors of lung cancer among never‐smokers.

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BACKGROUND Most existing evidence on secondhand smoke (SHS) exposure and lung cancer in never-smoking women comes from case-control studies, while findings from prospective cohort studies remain inconsistent. Regional variation in SHS-associated risk is poorly understood, and the potential impact of reducing SHS exposure in never-smoking women has not been quantified. METHODS We analyzed data from 20,401 never-smoking women in the Wenling lung cancer screening cohort (Zhejiang, China), applying Cox proportional hazards regression models to evaluate the association between SHS exposure and lung cancer risk. We further conducted a meta-analysis of published studies to examine regional variation and estimated the population attributable fraction (PAF) of SHS exposure for lung cancer incidence in never-smoking women. RESULTS SHS exposure was associated with an increased lung cancer risk (HR=1.52, 95% CI: 1.19-1.95). Lung cancer risk tended to increase with higher smoking intensity, with a linear trend observed for cigarettes per day, years of smoking, and pack-years of co-residents and colleagues (Poverall<0.05; Pnon-linear>0.05). In meta-analysis, the pooled relative risk was higher in Asia than in Europe and America [RR= 1.31 (95% CI: 1.20-1.43) vs 1.13 (95% CI: 1.04-1.23); Phet = 0.039]. The PAF suggested that 16.9% (95% CI: 11.6%-22.0%) of lung cancer cases among never-smoking women could be attributed to SHS exposure. CONCLUSIONS SHS exposure is a risk factor for lung cancer in never-smoking women, with stronger effects observed in Asian populations. Reducing SHS exposure could prevent a substantial proportion of lung cancer cases, underscoring the urgent need for strengthened tobacco control policies.

The proportion of lung cancer in never smokers is rising, especially among Asian women, but there is no effective early detection tool. Here, we developed a polygenic risk score (PRS), which may help to identify the population with higher risk of lung cancer in never‐smoking women. We first performed a large GWAS meta‐analysis (8595 cases and 8275 controls) to systematically identify the susceptibility loci for lung cancer in never‐smoking Asian women and then generated a PRS using GWAS datasets. Furthermore, we evaluated the utility and effectiveness of PRS in an independent Chinese prospective cohort comprising 55 266 individuals. The GWAS meta‐analysis identified eight known loci and a novel locus (5q11.2) at the genome‐wide statistical significance level of P < 5 × 10−8. Based on the summary statistics of GWAS, we derived a polygenic risk score including 21 variants (PRS‐21) for lung cancer in never‐smoking women. Furthermore, PRS‐21 had a hazard ratio (HR) per SD of 1.29 (95% CI = 1.18‐1.41) in the prospective cohort. Compared with participants who had a low genetic risk, those with an intermediate (HR = 1.32, 95% CI: 1.00‐1.72) and high (HR = 2.09, 95% CI: 1.56‐2.80) genetic risk had a significantly higher risk of incident lung cancer. The addition of PRS‐21 to the conventional risk model yielded a modest significant improvement in AUC (0.697 to 0.711) and net reclassification improvement (24.2%). The GWAS‐derived PRS‐21 significantly improves the risk stratification and prediction accuracy for incident lung cancer in never‐smoking Asian women, demonstrating the potential for identification of high‐risk individuals and early screening.

Although reproductive factors have been repeatedly associated with lung cancer risk, no study to date has directly evaluated the relationship with endogenous sex hormones nor with aromatase activity in postmenopausal never‐smoking women. A case‐control study of 397 incident lung cancer cases and their individually matched controls, nested within the Shanghai Women's Health Study, was conducted among postmenopausal women who were lifetime never smokers. Prediagnostic concentrations of sex hormones was quantitated using LC‐MS/MS assays in plasma. The product‐substrate molar ratio of estrone to androstenedione was used as an index of aromatase activity (IAA). Multivariable conditional logistic regression models were used to calculate odds ratios (ORs) for lung cancer. Baseline concentrations of estradiol, free testosterone and IAA were inversely associated with subsequent risk of lung cancer in multivariable‐adjusted models. When further adjusted for body mass index, the inverse association with estradiol was attenuated and no longer statistically significant, but the association with free testosterone and IAA remained. In analyses confined to participants having never used menopausal hormone therapy in 376 case‐control pairs, the inverse association with free testosterone and IAA was slightly strengthened. OR for the highest vs the lowest quartile of free testosterone was 0.55 (95% CI = 0.34‐0.90; Ptrend = .03), and the corresponding OR for IAA was 0.57 (95% CI = 0.34‐0.96; Ptrend = .04). Our study, for the first time, suggests that higher levels of circulating free testosterone and estimated aromatase activity may be associated with lower lung cancer risk in postmenopausal never‐smoking women.

Background: The etiology of lung cancer among never-smokers is unclear despite 15% of cases in men and 53% in women worldwide are not smoking-related. Metabolomics provides a snapshot of dynamic biochemical activities, including those found to be driving tumor formation and progression. This study used untargeted metabolomics with network analysis to agnostically identify network modules and independent metabolites in pre-diagnostic blood samples among never-smokers to further understand the pathogenesis of lung cancer. Methods: Within the prospective Shanghai Women’s Health Study, we conducted a nested case-control study of 395 never-smoking incident lung cancer cases and 395 never-smoking controls matched on age. We performed liquid chromatography high-resolution mass spectrometry to quantify 20,348 unique metabolic features in plasma. Because metabolic features are expected to be highly correlated and more likely to be involved in biological processes as a network of intertwined features than individually, we agnostically constructed 28 network modules using a weighted correlation network analysis approach. The associations between metabolite network modules and individual metabolites with lung cancer were assessed using conditional logistic regression models, adjusting for age, body mass index, and exposure to environmental tobacco smoke. We accounted for multiple testing using a false discovery rate (FDR) < 0.20. Results: We identified a network module of 122 metabolic features enriched in lysophosphatidylethanolamines that was associated with all lung cancer combined (p = 0.001, FDR = 0.028) and lung adenocarcinoma (p = 0.002, FDR = 0.056) and another network module of 440 metabolic features that was associated with lung adenocarcinoma (p = 0.014, FDR = 0.196). Metabolic features were enriched in pathways associated with cell growth and proliferation, including oxidative stress, bile acid biosynthesis, and metabolism of nucleic acids, carbohydrates, and amino acids, including 1-carbon compounds. Conclusions: Our prospective study suggests that untargeted plasma metabolomics in pre-diagnostic samples could provide new insights into the etiology of lung cancer in never-smokers. Replication and further characterization of these associations are warranted. Citation Format: Mohammad L. Rahman, Xiao-Ou Shu, Douglas Walker, Dean P. Jones, Wei Hu, Bu-tian Ji, Batel Blechter, Jason YY Wong, Qiuyin Cai, Gong Yang, Tu-Tang Gao, Wei Zheng, Nathaniel Rothman, Qing Lan. A nested case-control study of untargeted plasma metabolomics and lung cancer risk among never-smoking women in the prospective Shanghai Women’s Health Study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6056.

BACKGROUND Compared to women of other races who have never smoked, Black women have a higher risk of lung cancer. Whether neighborhood disadvantage, which Black women experience at higher rates than other women, is linked to never-smoking lung cancer risk remains unclear. This study investigates the association of neighborhood disadvantage and lung cancer risk in Black never-smoking women. METHODS AND MATERIALS This research utilized data from the Black Women's Health Study, a prospective cohort of 59,000 Black women recruited from across the US in 1995 and followed by biennial questionnaires. Associations of lung cancer incidence with neighborhood-level factors (including two composite variables derived from Census Bureau data: neighborhood socioeconomic status and neighborhood concentrated disadvantage), secondhand smoke exposure, and PM2.5 were estimated using Fine-Gray subdistribution hazard models. RESULTS Among 37,650 never-smokers, 77 were diagnosed with lung cancer during follow-up from 1995 to 2018. The adjusted subdistribution hazard ratio (sHR) of lung cancer incidence with ten unit increase in neighborhood concentrated disadvantage index was 1.30 (95 % CI: 1.04, 1.63, p = 0.023). Exposure to secondhand smoke at work was associated with increased risk (sHR = 1.93, 95 % CI: 1.21, 3.10, p = 0.006), but exposure to secondhand smoke at home and PM2.5 was not. CONCLUSION Worse neighborhood concentrated disadvantage was associated with increased lung cancer risk in Black women who never smoked. These findings suggest that non-tobacco-related factors in disadvantaged neighborhoods may be linked to lung cancer risk in Black women and that these factors must be understood and targeted to achieve health equity.

Background: Lung cancer rates among never-smoking women in Xuanwei and Fuyuan in China are among the highest in the world and have been attributed to the domestic use of smoky (bituminous) coal for heating and cooking. However, the key components of coal that drive lung cancer risk have not been identified. Objectives: We aimed to investigate the relationship between lifelong exposure to the constituents of smoky coal (and other fuel types) and lung cancer. Methods: Using a population-based case–control study of lung cancer among 1,015 never-smoking female cases and 485 controls, we examined the association between exposure to 43 household air pollutants and lung cancer. Pollutant predictions were derived from a comprehensive exposure assessment study, which included methylated polycyclic aromatic hydrocarbons (PAHs), which have never been directly evaluated in an epidemiological study of any cancer. Hierarchical clustering and penalized regression were applied in order to address high colinearity in exposure variables. Results: The strongest association with lung cancer was for a cluster of 25 PAHs [odds ratio (OR): 2.21; 95% confidence interval (CI): 1.67, 2.87 per 1 standard deviation (SD) change], within which 5-methylchrysene (5-MC), a mutagenic and carcinogenic PAH, had the highest individual observed OR (5.42; 95% CI: 0.94, 27.5). A positive association with nitrogen dioxide (NO2) was also observed (OR: 2.06; 95% CI: 1.19, 3.49). By contrast, neither benzo(a)pyrene (BaP) nor fine particulate matter with aerodynamic diameter ≤2.5μm (PM2.5) were associated with lung cancer in the multipollutant models. Conclusions: To our knowledge, this is the first study to comprehensively evaluate the association between lung cancer and household air pollution (HAP) constituents estimated over the entire life course. Given the global ubiquity of coal use domestically for indoor cooking and heating and commercially for electric power generation, our study suggests that more extensive monitoring of coal combustion products, including methylated PAHs, may be warranted to more accurately assess health risks and develop prevention strategies from this exposure. https://doi.org/10.1289/EHP4913

Key Points Question What is the association of metabolomic biomarkers with lung cancer in women who have never smoked? Findings In this case-control study of 275 never-smoking women with lung cancer and 289 never-smoking cancer-free women in China, the metabolite 5-methyl-2-furoic acid was correlated with dietary soy consumption and pathways including 1-carbon metabolism, oxidative stress, nucleotide metabolism, and inflammation and was significantly associated with lower lung cancer risk. Meaning These findings suggest that certain metabolites and pathways are associated with lower lung cancer risk in never-smoking women and biological processes linked to air pollution may be associated with higher lung cancer risk in this population.

Background: Previous studies have reported inconsistent associations between reproductive factors and lung cancer. Methods: We used data from the Japan Public Health Center-based Prospective Study, which included 400 incident lung cancer cases (305 adenocarcinoma) among 42,615 never-smoking women followed for a median of 21 years, to examine the associations of reproductive and hormonal factors with lung cancer by histological type using Cox proportional hazards models. Results: Longer fertility span (≥36 years vs. ≤32 years) was associated with increased risk of lung adenocarcinoma (HR, 1.48; 95% CI, 1.07–2.06, Ptrend = 0.01) but not with all lung cancer or nonadenocarcinoma. Similarly, late age at menopause (≥ 50 years) was associated with increased adenocarcinoma risk (vs. ≤ 47 years, HR, 1.41; 95% CI, 1.01–1.96, Ptrend 0.04). Compared with premenopausal women, women with natural menopause (HR, 1.99; 95% CI, 1.02–3.88) or surgical menopause (HR, 2.75; 95% CI, 1.33–5.67) were at increased risk of adenocarcinoma. In contrast, breastfeeding was associated with reduced risk of nonadenocarcinoma (HR, 0.51; 95% CI, 0.28–0.92). No significant association with parity, age at first birth, exogenous hormone use, or length of menstrual cycle was detected. Conclusions: Reproductive factors may play a role in lung carcinogenesis. Future studies that include estrogen and progesterone biomarkers may help clarify the role of endogenous hormones in lung carcinogenesis. Impact: Fertility span and age at menopause may be useful variables in developing risk prediction models for lung adenocarcinoma among nonsmoking women.

The mechanism of rapidly increased non‐small cell lung cancer (NSCLC) among never‐smoking Chinese women has not been elucidated. Ovarian sex steroid hormones have been suggested to counteract lung cancer development, and sex hormone‐binding globulin (SHBG) is essential in sex hormones regulation. This study aims to exploring single nucleotide polymorphisms (SNPs) in genomic regions associated with SHBG concentrations that contributed to never‐smoking female NSCLC.

Background/Aims We performed a large-scale, retrospective, nationwide, cohort study to investigate the risk factors for lung cancer among never-smoking Korean females. Methods The study data were collected from a general health examination and questionnaire survey of eligible populations conducted between January 1, 2003 and December 31, 2004; the data were acquired from the tailored big data distribution service of the National Health Insurance Service. After a 1-year clearance period, 5,860,922 of 6,318,878 never-smoking female participants with no previous history of lung cancer were investigated. After a median follow-up of 11.4 years, 43,473 (0.74%) participants were defined as “newly diagnosed lung cancer”. Results After adjusting for all variables at baseline, the variables older age, lower body mass index (BMI), less exercise, frequent alcohol drinking, meat-based diet, rural residence, and previous history of cancer were associated with a higher incidence of lung cancer. Low BMI (< 18.5 kg/m2: hazard ratio [HR], 1.33; 95% confidence interval [CI], 1.27 to 1.40) was a significant independent risk factor; as BMI decreased, HR increased. Negative associations between BMI and lung-cancer development were also observed after controlling for age (p for trend < 0.001). Drinking alcohol one to two times a week (HR, 1.25; 95% CI, 1.21 to 1.28) and eating a meat-based diet (HR, 1.08; 95% CI, 1.01 to 1.15) were associated with lung-cancer incidence. Conclusions Modifiable baseline characteristics, such as BMI, exercise, alcohol consumption, and diet, are risk factors for lung-cancer development among never- smoking females. Thus, lifestyle modifications may help prevent lung cancer.

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According to a NIH study, Lung cancer among individuals who have never smoked is more prevalent in women and occurs at an earlier age than in smokers. The rise in lung cancer rates among female non-smokers might be linked to radon inhalation and should be further investigated. Our theory is based on the differences in radon exposure between males and females, which can be attributed to the variations in time spent indoors versus outdoors. Over the past few years, the smoking rates have shown a steady decline in the United States and other developed countries. This decrease in smoking prevalence has led to a new shift in the primary risk factors associated with lung cancer. Although tobacco smoke historically served as the primary cause of lung cancer, the reduction in smoking rates has allowed other risk factors, such as radon exposure, to come to the forefront. Given that women in certain countries, on average, might spend more time indoors compared to men, they are potentially exposed to higher levels of radon. This increased exposure could explain the rising rates of lung cancer among female non-smokers. The theory is still in its nascent stages and requires further research and validation. However, if proven correct, it could significantly alter our understanding of lung cancer risk factors and lead to new prevention. It is therefore crucial to expedite the review and publication of this theory, given its potential implications for public health.

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Nearly one fourth of lung cancers occur among never-smokers and are predominately lung adenocarcinomas (LUADs) that are distinct from smoking-related cancers. Causal links between LUADs in never-smokers have been attributed to reactive oxygen species (ROS) arising from airborne fine particulate matter (PM2.5) and polycyclic aromatic hydrocarbons (PAHs). These effects are pronounced among East Asian women who experience massive exposures to PM2.5 and PAHs and have the highest incidence of LUADs in the world. We employed untargeted adductomics to establish ROS adduct signatures in human serum albumin (HSA) from lung cancer cases and controls from never-smokers in the Shanghai Women’s Health Study. Forty-seven HSA adducts were quantified by mass spectrometry, nine of which were selected for association with lung cancer, including Cys34 sulfoxidation products and disulfides of cysteine and homocysteine and two modifications to Lys525. Associated adducts include constituents of redox biology and one-carbon metabolism (OCM), which are pathways associated with lung cancer. Differences in adduct abundance between cases and controls and correlations of adducts with urinary PAHs and dietary factors provide additional evidence linking air pollutants, OCM, and redox biology with lung cancer in never-smokers.

Inflammation plays a key role in cancer development, and C-reactive protein (CRP) is often studied as a biomarker, though its association with lung cancer remains inconsistent. We previously reported an inverse association between plasma CRP levels and lung cancer development in never-smoking women in the Shanghai Women’s Health Study (SWHS). However, as CRP levels fluctuate with active inflammation, a single measurement may not accurately capture the inflammatory responses relevant to cancer development. DNA methylation-based inflammation risk scores (DNAm-IRS) provide a more stable, integrative measure of long-term inflammation. To date, only one prospective study, primarily in smokers, has examined DNAm-IRS and lung cancer risk, showing an inverse association after adjusting for DNAm-derived smoking patterns. In this study, we expand our previous research by more than doubling the number of lung cancer cases and controls and incorporating CRP-derived DNAm-IRS to investigate associations with lung cancer in never smokers. This nested case-control study, conducted within the prospective SWHS, included 683 never-smoking women with incident lung cancer and 683 never-smoking controls, matched on date of birth (±2 years) and sample collection time (±3 months). Four DNAm-IRS were calculated as the weighted sum of CRP-related CpG sites (52 for IRSLigthart, 1, 334 for IRSElnet, 1, 333 for IRSWielscher, and 32, 196 for IRSHillary) using established algorithms. Conditional logistic regression models were used to estimate odds ratios (OR) and 95% confidence intervals (CI), adjusting for age and body mass index. Among controls with available plasma CRP levels (n = 214), the Spearman correlation coefficients between biochemical CRP and DNAm-IRS derived from CRP were as follows: 0.20 (p=3.4×10-3) for IRSLigthart, 0.31 (p=4.6×10-6) for IRSElnet, 0.13 (p=6.7×10-2) for IRSWielscher, and -0.02 (p=7.4×10-1) for IRSHillary. Higher DNAm-IRS scores were associated with a reduced risk of lung cancer among never-smoking women. Specifically, each standard deviation (SD) increase in IRSWielscher was associated with a 13% lower risk of overall lung cancer (95% CI: 0.77-0.97; p=0.017) and a 17% lower risk of lung adenocarcinoma (95% CI: 0.71-0.97; p=0.018), the most common histologic subtype. Additionally, IRSLigthart was associated with a 15% lower risk of overall lung cancer (95% CI: 0.78-0.97; p=0.003). Our findings, along with prior research, suggest that certain aspects of CRP are paradoxically associated with a reduced risk of lung cancer in never-smokers or when analysis accounts for DNAm-derived smoking patterns. Further studies are warranted to replicate these findings and investigate the underlying biological mechanisms. Mohammad L. Rahman, Aishani Gargapati, Wei Zheng, Jason Y.Y Wong, Jianxin Shi, Charles E. Breeze, Batel Blechter, Wei Hu, Qiuyin Cai, Gong Yang, Jirong Long, Yu-Tang Gao, Nathaniel Rothman, Xiao-Ou Shu, Qing Lan. A prospective investigation on DNA methylation-based inflammation risk scores and lung cancer among never smokers: findings from the Shanghai Women’s Health Study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 2287.

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Over 200,000 individuals are diagnosed with lung cancer in the United States every year, with a growing proportion of cases, especially lung adenocarcinoma, occurring in individuals who have never smoked. Women over the age of 50 comprise the largest affected demographic. To understand the genomic drivers of lung adenocarcinoma and therapeutic response in this population, we performed whole genome and/or whole exome sequencing on 73 matched lung tumor/normal pairs from postmenopausal women who participated in the Women’s Health Initiative. Somatic copy number alterations showed little variation by smoking status, suggesting that aneuploidy may be a general characteristic of lung cancer regardless of smoke exposure. Similarly, clock-like and APOBEC mutation signatures were prevalent but did not differ in tumors from smokers and never-smokers. However, mutations in both EGFR and KRAS showed unique allelic differences determined by smoking status that are known to alter tumor response to targeted therapy. Mutations in the MYC-network member MGA were more prevalent in tumors from smokers. Fusion events in ALK, RET, and ROS1 were absent, likely due to age-related differences in fusion prevalence. Our work underscores the profound effect of smoking status, age, and sex on the tumor mutational landscape and identifies areas of unmet medical need.

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We previously identified 10 lung adenocarcinoma susceptibility loci in a genome-wide association study (GWAS) conducted in the Female Lung Cancer Consortium in Asia (FLCCA), the largest genomic study of lung cancer among never-smoking women to date. Furthermore, household coal use for cooking and heating has been linked to lung cancer in Asia, especially in Xuanwei, China. We investigated the potential interaction between genetic susceptibility and coal use in FLCCA. We analyzed GWAS-data from Taiwan, Shanghai, and Shenyang (1472 cases; 1497 controls), as well as a separate study conducted in Xuanwei (152 cases; 522 controls) for additional analyses. We summarized genetic susceptibility using a polygenic risk score (PRS), which was the weighted sum of the risk-alleles from the 10 previously identified loci. We estimated associations between a PRS, coal use (ever/never), and lung adenocarcinoma with multivariable logistic regression models, and evaluated potential gene-environment interactions using likelihood ratio tests. There was a strong association between continuous PRS and lung adenocarcinoma among never coal users (Odds Ratio (OR) = 1.69 (95% Confidence Interval (CI) = 1.53, 1.87), p=1 × 10-26). This effect was attenuated among ever coal users (OR = 1.24 (95% CI: 1.03, 1.50), p = 0.02, p-interaction = 6 × 10-3). We observed similar attenuation among coal users from Xuanwei. Our study provides evidence that genetic susceptibility to lung adenocarcinoma among never-smoking Asian women is weaker among coal users. These results suggest that lung cancer pathogenesis may differ, at least partially, depending on exposure to coal combustion products. Notably, these novel findings are among the few instances of sub-multiplicative gene-environment interactions in the cancer literature.

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Background. If lung cancer in never-smokers was a single disease entity, it would be the sixth most commonly occurring malignancy. Despite the population impact, its risk factors are poorly understood owing to a dearth of larger-scale, well-characterised studies. Methods. We pooled individual-participant data from 18 prospective cohort studies comprising 91,588 never smokers (55,452 women) aged 16-102 years at study induction. Participants were linked to national death registries. Results. A maximum of 17 years follow-up (mean 9.7) gave rise to 85 lung cancer deaths. Of the 19 potential determinants captured at baseline, only being older age (hazard ratio; 95% confidence interval per 10 year increase: 2.45; 2.11, 2.85), male (2.25; 1.46, 3.48), and having a high fruit and vegetable intake (2.29; 1.25, 4.17) were associated with elevated rates of lung cancer in this never-smoking group. No other substantial relationships were detected. Conclusions. Despite the number and breadth of potential risk factors featured in this multi-cohort study, there was no clear suggestion of new determinants of lung cancer in never-smokers. Impact. Our findings point to the need to explore the influence of risk factors additional to those included herein, particular in the field of genetics. Our unlikely finding for fruit and vegetable consumption warrants further testing.

Lung cancer is increasingly prevalent in the non-smoking population, with Household Air Pollution (HAP) recognised as a major contributor, and some evidence that women of South-Asian backgrounds are at greater risk than other demographics. A systematic review of available literature was performed to explore the risks of lung cancer posed by HAP for never-smokers in high-income countries. We identified three papers fulfilling our criteria, two conducted in Taiwan, and one in Hong Kong, with no identified studies fitting the criteria in Western countries. The review found that cooking-related HAP increases the risk of LCINS in Chinese women. There is a clear research gap regarding the impact of HAP on LCINS in high-income countries outside Taiwan and Hong Kong. Building on this evidence, the aim of this project is to determine whether South Asian households are exposed to higher levels of cooking-related HAP compared to households of White British ethnicity, leaving them at a greater risk of non-smoking lung cancer. Twenty households have been recruited, with White British, and South-Asian families equally represented among participants. Kitchen air quality is monitored for pollutants including PM1, PM2.5, PM10, gases including NOx, CO, and O3, VOCs and mould, using active and passive methods. Air sampling is conducted over a week, once in winter and once in summer to account for seasonal variation. Participants complete a daily diary noting activities related to cooking, cleaning and ventilation. A home survey is completed noting structural features e.g., age and style of house, layout of living spaces, floor coverings and renovation work.This study is ongoing, with the first round of data collection complete in January 2025. This data will include accurate, real time air quality measurements allowing for direct comparison with the daily activity diaries to assess the impact of cooking on kitchen air quality, as well as initial analysis of the impact of ethnicity and cultural practices on the quality of household air in non-smoking households.To date, data from eight houses has been collected, with 12 more scheduled. Initial Findings have shown that the use of gas cookers and hobs increases PM1, PM2.5, PM10, while also raising concentrations of NOx and O3. Homes using gas appliances frequently breached recommended NOx exposure levels. While air fryers and electric hobs also increase levels of PM1, PM2.5, PM10 during use, there is no corresponding increase in NOx or O3.To the best of our knowledge, this is the first UK study to explore how cooking practices affect the presence and concentrations of PM, VOCs and mould in household environments, with a focus on ethnicity and cultural practices. It will provide valuable data on how household air quality affects the risks of non-smoking lung cancer in a high-income country. Bría J. McAllister, Karen Brown, Samuel Cai, Sameena Khan. Non-smoking lung cancer: The impact of cooking-related household air pollution [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 3608.

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BACKGROUND Lung cancer has been the leading cause of cancer-related deaths among women in the United States since 1987, with many cases diagnosed at advanced stages, despite screening methods like low-dose CT scans. Although smoking remains the primary risk factor for lung cancer, nonsmoking women, who make up 20% of lung cancer cases in the United States, are also at risk. However, there are no established guidelines for screening nonsmoking women, even as lung cancer rates rise in this group. PURPOSE The study explores potential risk factors that may influence cancer staging and assesses the potential benefits of low-dose computed tomography (LDCT) screening for nonsmoking women. METHODOLOGY This retrospective chart review analyzed 300 female patients diagnosed with lung cancer between 2019 and 2023. Data collected included smoking status, age, risk factors like family history, secondhand smoke, pulmonary comorbidities, cancer stage, and histology. RESULTS A logistic regression model found that pulmonary comorbidities, a history of another cancer, and smoking status significantly influenced the likelihood of being diagnosed with advanced-stage (III or IV) lung cancer. Nonsmoking women with history of a lung comorbidity or history of cancer were more likely to be diagnosed at an earlier stage (I or II). CONCLUSION The study suggests that lung cancer screening (with LDCT) could enhance early detection and staging in high-risk nonsmoking women, especially those with pulmonary comorbidities or history of other cancers. IMPLICATIONS The results underscore the importance of expanding lung cancer screening criteria to include high-risk nonsmoking women, particularly those with pulmonary comorbidities or prior cancer history.

Low-dose computed tomography screening for lung cancer is currently targeted at heavy smokers or those with a family history of lung cancer. This study aimed to identify risk factors for lung cancer in individuals who do not meet the current lung cancer screening criteria as stipulated by the Taiwan Health Promotion Agency’s low-dose computed tomography (LDCT) screening policy. A cohort analysis was conducted on 12,542 asymptomatic healthy subjects aged 20–80 years old who voluntarily underwent LDCT scans from January 2016 to December 2021. Logistic regression demonstrated that several factors, including age over 55 years, female gender, a body mass index (BMI) less than 23, a previous history of respiratory diseases such as tuberculosis or obstructive respiratory diseases (chronic obstructive pulmonary disease [COPD], asthma), and previous respiratory symptoms such as cough or dyspnea, were associated with high-risk lung radiology scores according to LDCT scans. These findings indicate that risk-based assessments using primary data and questionnaires to identify risk factors other than heavy smoking and a family history of lung cancer may improve the efficiency of lung cancer screening.

In recent years, clinicians often encounter patients with multiple pulmonary nodules in their clinical practices. As most of these ground glass nodules (GGNs) are small in volume and show no spicule sign, it is difficult to use Mayo Clinic Model to make early diagnosis of lung cancer accurately, especially in large numbers of nonsmoking women who have no tumor history. Other clinical models are disadvantaged by a relatively high false-positive or false-negative rate. Therefore, there is an urgent need to establish a new model of predicting malignancy or benignity of pulmonary GGNs for the sake of making accurate and early diagnosis of lung cancer. Included in this study were GGNs surgically resected from patients who were admitted to Yiwu Central Hospital from January 2018 to March 2024, including both male and female patients, there is no gender specific issue. The nature of all these GGN tissues was confirmed pathologically. The case data were statistically analyzed to establish a mathematical prediction model, the prediction performance of which was verified by the pathological results. Altogether 261 GGN patients met the inclusion criteria. Using the results of logistic regression analysis, a mathematical prediction equation was established as follows: Malignant probability (mP) = ex/ (1 + ex); when mP was > 0.5, the GGN was considered as malignant, and when mP was ≤ 0.5, it was considered as benign. x= -2.46 + 1.032*gender + 1.85*mGGN + 1.40*VCS-0.0027*mean CT value of the nodule + 0.078*maximum diameter of the nodule, where e represents the natural logarithm; if the patient was a female, gender = 1 (otherwise = 0); if the pulmonary nodule was a mixed GGN, mGGN = 1 (otherwise = 0); if the pulmonary nodule had vascular convergence sign, VCS = 1 (otherwise = 0). The prediction performance of the mathematical prediction model was verified as follows: the negative prediction value was 0.97156 and the positive prediction value was 0.3800 in the model group versus 1 and 0.25 in the verification group. In this study, we identified female gender, mGGN, VCS, mean CT value and maximum nodule diameter as five key factors for predicting malignancy or benignity of pulmonary nodules, based on which we established a mathematical prediction model. This novel innovation may provide a useful auxiliary tool for predicting malignancy and benignity of pulmonary nodules, especially in women patients.

Mucosa‐associated lymphoid tissue (MALT) is a low‐grade lymphoma, but cases in which it has transformed into a high‐grade lymphoma have been reported, necessitating an accurate diagnosis. The patient was a 79‐year‐old nonsmoking Japanese female with history of ocular sarcoidosis. A computed tomography scan of her chest revealed a 35‐mm nodule in the left S1 + 2, contiguous with the lymph nodes. Additional nodules were observed around the left B5 and B10a. Bronchoscopy revealed stenosis caused by a white, glossy, elevated lesion with angiogenesis at the orifice of the left upper lobe bronchus. The biopsy specimen demonstrated the dominance of lymphoid cells and tested positive for CD20, CD79a, Bcl‐2, and IRTA‐1, which is consistent with the findings in MALT lymphoma. Therefore, in the presence of multiple infiltrative shadows along the bronchi with glossy elevated lesions without necrosis on bronchoscopy, it is important to consider MALT lymphoma as a differential diagnosis.

Pulmonary blastoma (PB) is an exceedingly rare and aggressive malignant lung neoplasm that has distinct biphasic morphology. In this report, we document rare manifestations and molecular alterations in PB. A 59-year-old non-smoker female, presented with cough and hemoptysis for 4 months. The high-resolution computed tomography chest scan showed a 3.5x2.7 cm mass in the basal segment of the left lung. Positron emission tomography and computed tomography revealed a fluorodeoxyglucose avid lobulated mass in the superior segment of the lower lobe of the left lung. On core biopsy, the diagnosis of pleomorphic carcinoma in a background of adenocarcinoma was made. A definite diagnosis of pulmonary blastoma was established on the left lung lobectomy specimen based on morphological and immunohistochemical findings. Post-surgical biopsy from the scalp swelling showed metastatic deposits. On Next Generation Sequencing (NGS), in addition to conventional CTNNB1 gene mutation, new pathogenic MYCN and ATM gene mutations were detected. Post-chemotherapy, the patient was doing well after 10 months of close follow-up. PB exhibited rare associations in the form of non-smoker status, scalp metastasis, and MYCN and ATM gene mutations on NGS in addition to conventional CTNNB1 gene mutation. Large cohort studies are required to discover the incidence, significance and therapeutic implications of these co-existing pathogenic molecular alterations in PB.

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BACKGROUND Invasive mucinous adenocarcinoma (IMA) is a rare subtype of lung adenocarcinoma, accounting for 3%-10% of cases. It is often associated with KRAS mutations or, in nonsmokers, NRG1 fusions. Approximately 20% of IMAs have unclear genomic backgrounds. This study aimed to clarify the genomic etiology of these cases through a retrospective molecular analysis and RNA sequencing. PATIENTS AND METHODS This study analyzed 107 cases of NSCLC that were treated by surgical resection at Aichi Cancer Center from 2009 to 2023, with a focus on IMAs. For cases with unclear genomic backgrounds, RNA sequencing was conducted to identify potential driver gene alterations, and the results were compared to those of known KRAS-positive cases. Statistical analyses, including Cox regression and Kaplan-Meier analyses, were used to evaluate risk factors, recurrence-free survival, and the prognosis. RESULTS In this study, 107 cases of resected IMA were analyzed. KRAS mutations were found in 70.1% of cases, followed by NRG1 fusions (9.2%), and other mutations. A novel fusion gene, ATP6V1H::LYN, was discovered in 1 case. RNA sequencing and a gene set enrichment analysis revealed distinct molecular pathways in KRAS-positive tumors, including the activation of oxidative phosphorylation and TNFα-NF-κB signaling. Tumors with no driver gene alterations exhibited a higher frequency of copy number variations and tumor mutational burden than KRAS and NRG fusion-positive cases. CONCLUSION IMAs are characterized by relatively higher incidences of harboring KRAS mutations and NRG fusion genes, revealing potential therapeutic targets including druggable mutations and immune-related markers, while highlighting the heterogeneous genomic background and utility of RNA sequencing.

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Background Altered expression of microRNAs (miRNAs) is implicated in lung carcinogenesis, but little research has investigated the association of miRNA alterations with lung cancer stage or smoking status. To identify such alterations in lung adenocarcinoma, we conducted miRNA profiling. Methods Lung adenocarcinoma specimens and paired nonneoplastic lung tissues from 58 patients who had received no preoperative therapy and underwent tumor resection from 1991 to 2006 were collected from tumor tissue banks. Thirty (52%) of the tumors were stage I and 28 (48%) stage II or higher. Twenty-five (43%) patients were nonsmokers and 33 (57%) were smokers. To identify miRNAs of which its expression was associated with disease stage and/or smoking status, we performed subgroup analyses based on disease stage and smoking status, alongside overall profiling of all samples. miRNA expression was profiled using a microarray kit in tumors and paired nonneoplastic lung tissues. We assessed the fold changes (FCs) and local false discovery rates (FDRs) for the intercept in addition to P values. Results Of the 706 miRNAs examined, 64 had overall altered expression. Of these, 36 (56%) were associated with all stages of adenocarcinoma in both smokers and nonsmokers. In stage-based analysis, 20 altered miRNAs were associated with stage I disease and 38 with stage II or higher disease. Of the 20 miRNAs associated with stage I adenocarcinoma, 4 were miR-200 family members, and miR-200b was the most highly upregulated. Analysis based on smoking status identified 38 altered miRNAs in nonsmokers and 6 altered miRNAs in smokers. Three miR-200 family members were significantly altered in nonsmokers. Among the miRNA alterations associated with stage I adenocarcinoma in nonsmokers, we found alterations in all 5 miR-200 family members (miR-200b, miR-200a, miR-141, miR-429, and miR-200c). Conclusions Our identification of miRNA alterations associated with early-stage lung adenocarcinoma in nonsmokers, especially alterations in the miR-200 family, suggests that these miRNAs may play a unique role in the early stages of lung carcinogenesis and progression in nonsmokers and that they may be useful as markers for the early detection of lung cancer.

Abstract Chronic exposure to heavy metals has been linked to lung, bladder, and prostate cancer risk, yet the evidence for nonsmoking, non-occupationally exposed individuals remains inconclusive. We conducted a preliminary investigation within the EPIC (European Prospective Investigation into Cancer and nutrition) Florence cohort to compare pre-diagnostic serum levels of Cd, Co, Cr, Mn, Pb, and Tl, among subjects who developed lung, bladder, or prostate cancer during follow-up, and among matched non-cancer controls. For each cancer type, we included 50 cases paired with 50 same-age and -sex non-cancer subjects selected among never and long former smokers. Serum heavy metals levels were quantified using inductively coupled plasma mass spectrometry. Median concentrations did not significantly differ between cancer cases and matched controls for any heavy metal. This exploratory, population-based investigation does not support a role of heavy metals in the etiology of lung, bladder, and prostate cancer among nonsmokers.

Lung cancer is the most common cause of death among all cancer deaths. Adenocarcinoma of the lung is commonly seen in females and nonsmokers. It is a subtype of non-small cell lung cancer (NSCLC). The lesions are more peripherally located and tend to be smaller. Histologically, adenocarcinoma is present as atypical adenomatous hyperplasia (precursor lesion) which progresses to adenocarcinoma in situ and later develops into invasive adenocarcinoma. Adenocarcinoma of the lung is diagnosed by histopathological confirmation via thoracocentesis of pleural effusion, excisional biopsy of an accessible lymph node, bronchoscopy guided lung biopsy, transthoracic needle aspiration, sputum cytology, CT-guided biopsy, medical as well as video-assisted thoracoscopy. This case series comprises three patients with primary lung adenocarcinoma who had been presented with atypical clinical features and emphasised challenges faced in diagnosis.

BACKGROUND The effects of long-term PM2.5 exposures since 1968 on adenocarcinoma lung cancer (AdLC) were not studied before. METHODS This case-referent study used nationwide cancer registry data since 1997 and air pollution data since 1968 in Taiwan to estimate risks of 30-year PM2.5 exposures on AdLC. Cases were all AdLC, while references were all non-AdLC. Individuals' 30-year PM2.5 exposures were estimated by PM2.5 levels at their residence for 30 years prior their diagnosis dates. We applied multiple logistic regression analyses to estimate PM2.5 exposures on incidence rate ratios (IRRs) between cases and references, adjusting for sex, age, smoking, cancer stage, and EGFR mutation. RESULTS Elevation in annual ambient PM2.5 concentrations since 1968 were associated with increase in annual age-adjusted AdLC incidence since 1997. AdLC incidences were higher among females, nonsmokers, the elderly aged above 65, cases of stages IIIB to IV, and EGFR mutation. Study subjects' PM2.5 exposures averaged at 33.7±7.4 μg/m3 with 162±130 high PM2.5 pollution days over 30 years. Multiple logistic models showed an increase in 10 μg/m3 of PM2.5 exposures were significantly associated with 1.044 of IRR between all AdLC and all non-AdLC cases during 2011-2020. Our models also showed that females and nonsmokers and adults less than 65 years had higher IRRs than their respective counterparts. Restricted analyses showed similar effects of PM2.5 exposures on IRRs between stage 0-IIIA and IIIB-IV cases and between EGFR+ and EGFR- cases. CONCLUSIONS Long-term exposures to PM2.5 over 30 years were associated with elevated risks of AdLC against non-AdLC, regardless of gender, age, smoking status, cancer stage, or EGFR mutation.

Background: Lung adenocarcinoma—an aggressive and life-threatening malignancy—is a type of non–small-cell lung cancer. Despite medical advancements, the prognosis of lung adenocarcinoma remains unfavorable, likely because of its heterogeneous nature. Furthermore, few subtype-specific treatments are available for lung adenocarcinoma. This study was conducted to explore the molecular subtypes of lung adenocarcinoma. Methods: We performed a joint analysis of transcriptome and proteome data from East Asian patients with lung adenocarcinoma (nonsmokers, 86.5%). Results: Four novel subtypes were identified based on distinct molecular characteristics: subtypes I, II, III, and IV. In patients with subtype I lung adenocarcinoma, eukaryotic translation initiation factor 4 gamma 1 activates cell proliferation; inhibiting this factor suppresses tumor growth, and reducing its level induces autophagy. Subtype II is characterized by Kristen rat sarcoma viral oncogene homolog-activating oncogenesis; the onset age of this subtype is the lowest among all subtypes. Subtype III manifests as an advanced disease at diagnosis; it is characterized by a core serum response-related oncogenic signature, which indicates poor overall survival in Western patients with lung cancer. Subtype IV is more common in men than in women; it has astroglial characteristics. A Connectivity Map analysis revealed that the oncogenic expression patterns corresponding to subtypes I, II, III, and IV can be reversed by the inhibitors of Inhibitor of κB (IκB) kinase (eg, withaferin A), mammalian target of rapamycin (eg, everolimus), Src proto-oncogene (Src) (eg, saracatinib), and Transforming Growth Factor (TGF)-β/Smad (eg, LY-364947), respectively. Conclusion: This study introduced an innovative multiomics data analysis pipeline. Using this approach, we successfully identified four molecular subtypes of lung adenocarcinoma and their candidate therapeutic agents. The newly identified subtypes can be combined with the current biomarkers to generate a comprehensive roadmap for treatment decision-making.

Background Sex-related differences in cancer epidemiology, tumor biology, immune system activity, and pharmacogenomics have been suggested to be important considerations for precision cancer control. Here we elucidated systematically sex biases in genetic variants, gene expression profiles, and immunological landscapes of lung adenocarcinoma patients (LUADs) with different ancestry and smoking status. Methods Somatic mutation and mRNA expression data of Asian and Non-Asian LUADs were obtained from public databases. Sex-biased genetic mutations, gene expression, biological pathways, and immune infiltration were identified in the context of smoking status and race. Results Among nonsmokers, male-biased mutations were prevalent in Asian LUADs, while few sex-biased mutations were detected in Non-Asian LUADs. EGFR was the only mutation whose frequency was significantly higher in females than males in both Asian and Non-Asian nonsmokers. More genes exhibited sex-biased expression in Non-Asian LUADs compared to Asian LUADs. Moreover, genes distinctly expressed in females were mainly related to immune-related pathways, whereas those in males were more involved in activation of DNA repair, E2F_targets, and MYC_targets pathways. We also detected sex-specific immune infiltration in the context of genetic variation. In EGFR -mutant LUADs, males had a significantly increased infiltration of CD8 + T cells, whereas resting CD4 + memory T cells were more abundant in females. Additionally, in KRAS -mutant LUADs, CD8 + and CD4 + T cells were more abundant in females than males. In addition, we detected all female patients with high SCGB3A2 expression were exclusively sensitive to immunotherapy, while this phenomenon was not observed in male patients. Conclusions Our findings provided evidence that sex-related molecular and cellular components are involved in shaping tumor distinct genetic and immune features, which might have important impact on personalized targeted and immune therapy.

Lung cancer remains the leading cause of cancer-related deaths globally. While smoking-related lung cancers still account for most cases and cause approximately 100,000 deaths annually in the USA, smoking rates have been declining for decades. Lung cancer in never-smokers (LCINS), which tends to affect women and Asian populations, is now the fifth most common cause of cancer-related deaths worldwide. In 2023, over 20,000 lung cancer deaths in the USA were projected to occur in never-smokers, making LCINS the eighth leading cause of cancer-related mortality in the country. As the number of LCINS cases rises, it becomes increasingly important to explore the unique causes and characteristics of the disease, which calls for tailored diagnostic approaches and personalized treatment plans. Lung adenocarcinoma (LUAD) can present with atypical imaging features that often resemble benign conditions, including pneumonia, lung abscesses, post-infectious scarring, atelectasis, mediastinal masses, emphysema, and granulomatous disease. This variability in presentation can hinder accurate diagnosis and potentially delay timely treatment. While lung cancer is uncommon in younger individuals, with only 5.6% of new cases occurring in those under 54 years old, clinicians should maintain a high index of suspicion, as early detection is essential, and atypical cases can be easily missed. Here, we present a complex case involving an unusual radiologic manifestation of a lung mass, in which tuberculosis was initially considered the primary differential diagnosis.

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BACKGROUND Although smoking is a primary cause of lung cancer, females are overrepresented among never-smokers with the disease. The mutational landscape of adenocarcinoma in never-smoking females has been extensively profiled; however, there is little knowledge about genomic alterations in non-adenocarcinoma non-small-cell lung cancer (NA-NSCLC). In the study, we reviewed the status of oncogenic drivers of NA-NSCLC in these populations. MATERIALS AND METHODS Comprehensive genomic profiling was performed on DNA extracted from formalin-fixed, paraffin-embedded sections of 52 NA-NSCLC tissues, including 35 squamous cell carcinomas (SQCCs), 11 adenosquamous carcinomas, 5 pulmonary sarcomatoid carcinoma, and 1 large cell carcinoma by next-generation sequencing within a panel of 68 cancer-related genes. RESULTS Mutations of the common oncogenic drivers (EGFR, KRAS, ALK, ROS1, MET, RET, and ERBB2) occurred in 61.5% of cases. The frequency of well-established targets (EGFR and ALK), new targets without widely available therapies (MET and ERBB2), and potentially actionable targets (RET and DDR2) in SQCCs of female never-smokers was significantly higher than that in The Cancer Genome Atlas dataset. There were 31%, 82%, and 80% of cases with SQCC, adenosquamous carcinoma, and pulmonary sarcomatoid carcinoma, respectively, harboring at least one of the following targets: EGFR, ALK, ERBB2, and MET. Approximately 78% (7/9) of the patients responded to various targeted treatments. CONCLUSION Female never-smokers with NA-NSCLC in this study had a high frequency of currently known or potentially actionable oncogenic alterations and could benefit from targeted therapy. Our study also provides evidence for the recommendation of molecular analysis in never-smoking female SQCC.

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INTRODUCTION Lung cancer remains a leading cause of cancer incidence, yet, in Greece, country-level registry-based data are limited. We have thus investigated the epidemiology of lung cancer and its trends in the George Papanikolaou Hospital, Northern Greece over 18 years (2000–2018). METHODS We analyzed all the cases reported in the Bronchoscopy Unit of the Hospital for the period 2000–2018. In total, 15131 subjects (12300 males and 2831 females) that presented with a mass in the imaging, were submitted to bronchoscopy. Characteristics of patients such as age, sex, smoking history and occupation were collected. Statistical analysis was performed with SPSS 21.0 software package. RESULTS Among all subjects, a total of 5628 (37.2%; mean age: 65.85 ± 9.6 years) cases of primary lung cancer were identified with a male to female ratio of 2:1 (41.1% to 20.4%) (p<0.001). Squamous cell lung cancer was the most common type of lung cancer identified in this population (44%) with a higher proportion in males compared to females (p<0.001). Furthermore, adenocarcinoma was mostly observed in female non-smokers compared to males (p<0.001). The majority of lung cancer cases were identified in patients occupied with agriculture and livestock breeding (41.1%). The mean age at lung cancer diagnosis was 66.13 ± 9.19 years for the whole study population. Lung cancer cases observed with a higher mean of 43.93 ± 10.84 years of smoking compared to cancer-free patients with 39.64 ± 13.23 years of smoking (p<0.001). CONCLUSIONS Apart from smoking, demographic characteristics including age, sex and occupation appear to have an impact on lung cancer development in this population. Smoking history alone could not predict the development of lung cancer in the studied northern Greek population.

Lung cancer is the primary and third most frequently detected form of cancer in both males and females. The present study tries to perform integrated analysis in male as well as female patients inclusively both smoker and non-smokers. This study aims to identify diagnostic biomarkers and therapeutic targets for lung cancer patients using human microarray profile datasets. Differentially expressed genes (DEGs) were identified using a PPI network from the String database, and major modules or clusters were extracted using MCODE. The Cytohubba plug-in was used to find hub genes from the PPI network using centralities approaches. Twenty significant hub genes (CCND1, CDK1, CCNB1, CDH1, TP53, CTNNB1, EGFR, ESR1, CDK2, CCNA2, RHOA, EGF, FN1, HSP90AA1, STAT3, JUN, NOTCH1, IL6, SRC, and CD44) were identified as promising diagnostic biomarkers and therapeutic targets for lung cancer treatment. Survival analysis and hub gene validation were also conducted. GO enrichment and pathway analysis were conducted to identify their important functions. These hub genes were also used to identify targeted drugs. The findings suggest that the identified genes have the potential to be used as diagnostic biomarkers and therapeutic targets for lung cancer treatment.

Introduction: PIONEER (NCT01185314) was a prospective, multinational, epidemiological study of epidermal growth factor receptor (EGFR) mutations in patients from Asia with newly diagnosed advanced lung adenocarcinoma. Methods: Eligible patients (aged ≥20 years) had untreated stage IIIB/IV adenocarcinoma. The EGFR mutation status (primary end point: positive, negative, or undetermined) of tumor samples (biopsy, surgical specimen, or cytology) was determined (Scorpion amplification refractory mutation system). EGFR mutation frequency was calculated and compared between demographic and clinical subgroups. Results: Of 1482 patients from seven Asian regions, 43.4% of patients were female, median age was 60 years (range, 17–94), and 52.6% of patients were never-smokers. EGFR mutation status was evaluable in tumors from 1450 patients (97.8%) (746 [51.4%] positive; 704 [48.6%] negative). Country, sex, ethnicity, smoking status, pack-years (all p < 0.001), disease stage (p = 0.009), and histology type (p = 0.016) correlated significantly with EGFR mutation frequency. Mutation frequency was 61.1% in females, 44.0% in males; lower in patients from India (22.2%) compared with other areas (47.2%–64.2%); highest among never-smokers (60.7%); and decreased as pack-year number increased (>0–10 pack-years, 57.9%; >50 pack-years, 31.4%) (similar trend by sex). Ethnic group (p < 0.001) and pack-years (p < 0.001) had statistically significant associations with mutation frequency (multivariate analysis); sex was not significant when adjusted for smoking status. Conclusion: PIONEER is the first prospective study to confirm high EGFR mutation frequency (51.4% overall) in tumors from Asian patients with adenocarcinoma. The observed high mutation frequency in demographic/clinical subgroups compared with white populations suggests that mutation testing should be considered for all patients with stage IIIB/IV adenocarcinoma, even males and regular smokers, among Asian populations.

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Genetic aberrations in tumor driver genes provide specific molecular targets for therapeutic intervention, which can greatly improve therapeutic outcomes. Here, we analyzed the mutational frequency of EGFR and KRAS gene, as well as EML4-ALK rearrangement and summarized the clinicopathological characters of Chinese lung cancer patients. We detected the mutation spectrum of 1033 primary lung cancer patients. The analyzed clinicopathological parameters included gender, age at diagnosis, smoking status, pathological TNM stage, tumor morphology and location, visceral pleural invasion and histological type. A total of 618 patients had mutations in EGFR or KRAS gene as well as rearrangement of EML4-ALK. Exon 19 deletions and L858R in the EGFR gene were the most frequent mutations. Left-side lung cancer was more common in female patients carrying the KRAS mutation. Rearrangement of EML4-ALK was more common in non-tobacco-using male patients, who also exhibited a higher likelihood of visceral pleura invasion. Elderly females who never smoked and possessed 1–20 mm stage I adenocarcinomas in the right side exhibited a higher frequency of EGFR mutations. Elderly male smokers with right lung tumors were viable candidates for KRAS mutation screening.

Background A recent report suggested that women who had been taking hormone replacement therapy (hrt) experienced significantly decreased survival after a lung cancer diagnosis. Given the large cohort of women who have received hrt, it is important to try to confirm that association. Methods We reviewed female patients diagnosed with lung cancer at our institution between January 1999 and December 2003 for age at diagnosis, disease stage, treatment, smoking history, hrt, performance status, weight loss, age at menopause, and overall survival. Patients were excluded if they had small-cell lung cancer or an unknown primary cancer, or if they had had previous or synchronous non-lung, non-skin cancers. Statistical analysis used the chi-square test for categorical variables and the Kaplan–Meier method and Cox regression model for univariate and multivariate analyses of overall survival. Results Of 397 eligible patients, most (68%) were stage iii or iv. The group included very few never-smokers (5%). The proportion of patients with experience of prior or current hrt was 29%, and no effect on overall survival was observed. Median survival was 13 months in the non-hrt group and 14 months in the hrt group. Significant factors predicting for overall survival included performance status, stage, and weight loss. Conclusions Stage, performance status, and weight loss are the most powerful predictors of survival for women with non-small-cell lung cancer. As compared with non-hrt users, patients with prior hrt use did not have inferior outcomes, failing to duplicate previously published results.

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The validity of the linear-no-threshold (LNT) model in radiation regulation remains contested. Although extensive experimental evidence challenges it, epidemiological studies—especially cohort and case-control designs—are still used to justify its application. This article focuses on a key methodological limitation of individual-level epidemiological studies, particularly the reported link between residential radon and lung cancer. Pooled case-control analyses suggest a linear dose-response relationship consistent with the LNT model, while ecological studies show mixed results. Case-control data are often deemed more reliable than ecological studies, but their validity requires reexamination. A central issue is the neglect of radon’s role within the broader context of indoor air pollution. Because more than 90% of radon decay products adhere to airborne particles, measured radon levels can effectively serve as a proxy for indoor particulate matter (PM), which is a complex mixture of harmful compounds. Since PM2.5 is a well-established lung carcinogen, the observed radon-lung cancer association may reflect PM2.5 effects rather than radon itself. This confounding is weaker in ecological studies, which use regional averages less directly tied to individual homes. When experimental evidence, evolutionary reasoning, and ecological findings contradict individual-level studies, it is possible that the latter are inherently flawed by design. Continued reliance on epidemiological studies to uphold the LNT model should therefore be critically reconsidered.

Introduction: Lung cancer is the most diagnosed type of cancer and the leading cause of death around the world. The most important risk factor for lung cancer is tobacco smoking. However, there are a lot of other lung cancer risk factors, which include: second-hand smoke exposure, environmental exposures (indoor and outdoor air pollution), occupational exposures, genetic predisposition, and previous lung disease. In this study, we would like to present the actual state of knowledge about the influence of radon as well as other indoor air pollutants on the prevalence of lung cancer. State of knowledge: We analyzed nineteen studies in terms of the impact of indoor air pollution on morbidity and mortality caused by lung cancer. The authors of the included studies agree that both radon and other household air pollution (HAP) increase risk of the lung cancer. HAPs are formed during the combustion of solid fuels (i.e. charcoal, wood). Indoor air pollution can cause in the lungs chronic inflammation, cells damage and their proliferation, depletion of antioxidants, impairment of defense mechanisms, production of reactive oxygen species as well as genetic mutations. Radon, on the other hand, emits alpha radiation, which can affect the respiratory epithelium and produce various cytotoxic and genotoxic effects, which promote carcinogenesis. The risk of lung cancer rises by approximately 6-16% per 100 Bq/m3 increase in long-time average residential radon concentration.  Conclusions: Radon and other indoor air pollutants are crucial lung cancer risk factors. It is essential to reduce HAPs production, especially in rural areas, where many people still use coal, wood, or straw for household heating and cooking. Moreover, there are regions where is a need to improve ventilation as well as to switch to clean fuel sources, such as gas and electricity. These activities will contribute to reducing the concentration of HAPs in buildings and decreasing the risk of lung cancer.

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Chiang Mai province of Thailand is known for having the highest natural background radiation in the country, as well as being recognized as one of the world’s most polluted cities for air quality. This represents the major contributor to the development of lung cancer. This research aims to estimate the comprehensive dose of both internal and external exposure due to natural background radiation and related health perspectives in the highly polluted area of Chiang Mai. The average values of indoor radon and thoron concentrations in 99 houses over 6 months were 40.8 ± 22.6 and 17.8 ± 16.3 Bq/m3, respectively. These results exceed the worldwide value for indoor radon and thoron (40 and 10 Bq/m3), respectively. During burning season, the average values of indoor radon (56.7 ± 20 Bq/m3) and thoron (20.8 ± 20.4 Bq/m3) concentrations were higher than the world-wide averages. The radon concentration in drinking water (56 samples) varied from 0.1 to 91.9 Bq/L, with an average value of 9.1 ± 22.8 Bq/L. Most of the drinking water samples (87%) fell below the recommended maximum contamination limit of 11.1 Bq/L. The average values of natural radionuclide (226Ra, 232Th and 40K) in 48 soil samples were 47 ± 20.9, 77.9 ± 29.7 and 700.1 ± 233 Bq/kg, respectively. All values were higher than the worldwide average of 35, 30 and 400 Bq/kg, respectively. The average value of outdoor absorbed gamma dose rate (98 ± 32.5 nGy/h) exceeded the worldwide average of 59 nGy/h. Meanwhile, the average activity concentrations of 226Ra, 232Th and 40K in 25 plant food samples were 2.7 ± 0.1, 3.2 ± 1.6 and 1000.7 ± 1.9 Bq/kg, respectively. The 40K concentration was the most predominant in plant foods. The highest concentrations of 226Ra, 232Th and 40K were found in Chinese cabbage, celery and cilantro, respectively. The total annual effective dose for residents in the study area varied from 0.6 to 4.3 mSv, with an average value of 1.4 mSv. This indicates a significant long-term public health hazard due to natural background radiation and suggests a heightened radiation risk for the residents. The excess lifetime cancer risk value (5.4) associated with natural background radiation was found to be higher than the recommended value. Moreover, the number of lung cancer cases per year per million average of 25.2 per million persons per year was in the limit range 170–230 per million people. Overall, our results will be used for future decision making in the prevention of lung cancer risk associated with natural background radiation.

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A BSTRACT This systematic review aggregates data from 15 articles published between 2000 and 2025 in PubMed, Scopus, and Google Scholar to discuss environmental exposures for lung cancer risk among never-smokers in Nigeria. The main drivers are indoor radon (levels 5–50 Bq/m 3 , occasionally higher than Nigeria’s 11.1 Bq/m 3 threshold in mining populations but within World Health Organization (WHO) 100 Bq/m 3 , associated with higher lung cancer risk by alpha radiation-induced DNA damage); particulate matter (PM 2.5 at 15–40 μg/m 3 in urban settings like Lagos and Port Harcourt, with hazard ratios 1.12–1.24 for lung cancer mortality per 10 μg/m 3 increase through inflammation and oxidative stress); household air pollution from biomass combustion (responsible for 10%–15% of never-smoker cases in rural settings, driven by carcinogens like polycyclic aromatic hydrocarbons); and asbestos (predominantly occupational in construction and mining but with rare environmental evidence but established causation of chronic inflammation leading to carcinogenesis). These exposures combined account for 15%–30% of lung cancer in Nigerian never-smokers. Although concentrations are predominantly below WHO guideline levels (100 Bq/m 3 for radon, 25 μg/m 3 for PM 2.5 ), localized exceedance and synergies with other factors underscore the need for stepped-up monitoring, cleaner energy transition, and public policy to diminish Nigeria’s industrial and rural lung cancer burden.

Purpose This study constructs a lung cancer risk index (LCRI) that incorporates many modifiable risk factors using an easily reproducible and adaptable method that relies on publicly available data. Methods We used meta-analysis followed by Analytic Hierarchy Process (AHP) to generate a lung cancer risk index (LCRI) that incorporates seven modifiable risk factors (active smoking, indoor air pollution, occupational exposure, alcohol consumption, secondhand smoke exposure, outdoor air pollution, and radon exposure) for lung cancer. Using county-level population data, we then performed a case study in which we tailored the LCRI for use in the state of Illinois (LCRI IL ). Results For both the LCRI and the LCRI IL , active smoking had the highest weights (46.1% and 70%, respectively), whereas radon had the lowest weights (3.0% and 5.7%, respectively). The weights for alcohol consumption were 7.8% and 14.7% for the LCRI and the LCRI IL , respectively, and were 3.8% and 0.95% for outdoor air pollution. Three variables were only included in the LCRI: indoor air pollution (18.5%), occupational exposure (13.2%), and secondhand smoke exposure (7.6%). The Consistency Ratio (CR) was well below the 0.1 cut point. The LCRI IL was moderate though significantly correlated with age-adjusted lung cancer incidence ( r  = 0.449, P  < 0.05) and mortality rates ( r  = 0.495, P  < 0.05). Conclusion This study presents an index that incorporates multiple modifiable risk factors for lung cancer into one composite score. Since the LCRI allows data comprising the composite score to vary based on the location of interest, this measurement tool can be used for any geographic location where population-based data for individual risk factors exist. Researchers, policymakers, and public health professionals may utilize this framework to determine areas that are most in need of lung cancer-related interventions and resources.

1. Overview 2. Screening and diagnosis 2.1 Risk factors for lung cancer 2.1.1 Smoking and passive smoking 2.1.2 Indoor pollution 2.1.3 Indoor radon exposure 2.1.4 Outdoor air pollution 2.1.5 Occupational factors 2.1.6 Family history of lung cancer and genetic susceptibility 2.1.7 Other factors 2.2 Screening for high-risk population 2.3 Clinical manifestations 2.3.1 Symptoms arising from local growth of primary tumor itself 2.3.2 Symptoms of primary tumor invading adjacent organs and structures 2.3.3 Symptoms caused by distant metastasis of tumors 2.3.4 Extrapulmonary manifestations of lung cancer 2.4 Physical examination 2.5 Accessory examination 2.5.1 Laboratory examination 2.5.2 Imaging examination 2.5.3 Endoscopy and other examinations 2.6 Histopathological examination 2.6.1 Diagnostic criteria 2.6.2 Specifications for diagnosis 2.6.3 Pathological diagnosis report 3. Pathological type and stage of lung cancer 3.1 WHO’s 2015 standard 3.1.1 Squamous cell carcinoma 3.1.2 Adenocarcinoma 3.1.3 Neuroendocrine carcinoma 3.1.4 Other types of lung cancer 3.1.5 Immunohistochemistry and special staining 3.2 Stage of lung cancer

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1992 marks the sixtieth anniversary of the publication of the first paper on the production of cancer by pure hydrocarbons, by the team at the Chester Beatty Research Institute headed by Professor Kennaway. Studies on polycyclic aromatic hydrocarbons and other chemical carcinogens continued to thrive under his leadership in succeeding years at the Chester Beatty and beyond, into his ‘retirement’ in 1946. He played a key role in stimulating research on factors contributing to the epidemic of lung cancer that became apparent by then, and with the support of the Medical Research Council (MRC) and other organizations he directed a small team working on analytical and epidemiological studies in a makeshift laboratory at St Bartholomew's Hospital. Published work included the identification and determination of benzo(a)pyrene in domestic soot, urban air pollution, motor vehicle exhausts and cigarette smoke, also arsenic in urban air and cigarette smoke, radon in indoor air and carbon deposits in human lungs. Such studies have been pursued in other laboratories around the world since then, and many of the lines of enquiry are traceable back to the pioneering work of the team at the Chester Beatty 60 years ago.

Though indoor air pollution (IAP) is associated with elevated lung cancer risk, an integrated measure is imperative to thoroughly investigate this association. The interplay between sex and IAP on lung cancer remains unclear. We conducted a population‐based case‐control study in Jiangsu Province, China, from 2003 to 2010, with 2871 lung cancer cases and 8019 controls. Exposures and covariates information were collected via in‐person interviews using a standardized questionnaire. An integrated weighted risk score (WRS), accounting for the effect sizes of each source of IAP, was introduced. Unconditional logistic regression was employed to estimate adjusted odds ratios (aORs) and their 95% confidence intervals (CIs). Interactions between sex and IAP by tobacco smoking status were evaluated. Environmental tobacco smoking (ETS) (aOR = 1.54, 95% CI: 1.40, 1.69), poor ventilation (aOR = 1.18, 95% CI: 1.07, 1.30), and coal used for cooking (aOR = 1.27, 95% CI: 1.15, 1.41) were associated with lung cancer. Dose‐response relationships between lung cancer and WRS were observed, with p for trend less than 0.001. aOR for individuals at the highest quartile of the WRS of IAP was 1.74 (95% CI: 1.52, 2.00) compared to the lowest quartile. The associations were more profound among never‐smokers than ever‐smokers. Females tended to be more vulnerable to IAP, and sex interacted with IAP beyond multiplicativity on the odds scale. IAP is associated with lung cancer, with a stronger impact among never‐smokers. An interaction between IAP and sex was observed. These results underscore the importance of controlling IAP, especially ETS in order to reduce the risk of lung cancer.

(1) Background: Cooking and burning incense are important sources of indoor air pollutants. No studies have provided biological evidence of air pollutants in the lungs to support this association. Analysis of pleural fluid may be used to measure the internal exposure dose of air pollutants in the lung. The objective of this study was to provide biological evidence of indoor air pollutants and estimate their risk of lung cancer. (2) Methods: We analyzed 14 common air pollutants in the pleural fluid of 39 cases of lung adenocarcinoma and 40 nonmalignant controls by gas chromatography-mass spectrometry. (3) Results: When we excluded the current smokers and adjusted for age, the adjusted odds ratios (ORs) were 2.22 (95% confidence interval CI = 0.77–6.44) for habitual cooking at home and 3.05 (95% CI = 1.06–8.84) for indoor incense burning. In females, the adjusted ORs were 5.39 (95% CI = 1.11–26.20) for habitual cooking at home and 6.01 (95% CI = 1.14–31.66) for indoor incense burning. In pleural fluid, the most important exposure biomarkers for lung cancer were naphthalene, ethylbenzene, and o-xylene. (4) Conclusions: Habitual cooking and indoor incense burning increased the risk of lung adenocarcinoma.

Lung cancer and chronic obstructive pulmonary disease (COPD) are closely linked diseases. In Xuanwei, China, the extremely high incidence and mortality rates of lung cancer and COPD are associated with exposure to household smoky coal burning. Previous studies found that telomere length was related to lung disease. The objective of this study is to investigate the relationship of peripheral blood leukocyte telomere length to both lung cancer and COPD, as well as indoor coal smoke exposure in Xuanwei. We measured telomere length using quantitative polymerase chain reaction (qPCR) in peripheral blood leukocytes of 216 lung cancer patients, 296 COPD patients, and 426 healthy controls from Xuanwei. The telomere length ratios (mean ± SD) in patients with lung cancer (0.76 ± 0.35) and COPD (0.81 ± 0.35) were significantly shorter than in that of controls (0.95 ± 0.39). Individuals with the shortest tertile telomere length had 3.90- and 4.54-fold increased risks of lung cancer and COPD, respectively, compared with individuals with the longest tertile telomere length. No correlation was found between telomere length and pack-years of smoking. In healthy subjects, coal smoke exposure level affected telomere length. Lung function was positively and negatively associated with telomere length and environmental exposure, respectively, when combination the control and COPD groups. The result suggests that shortened telomere length in peripheral blood leukocytes was associated with lung cancer and COPD and might be affected by coal smoke exposure level in Xuanwei. Whether variation in telomere length caused by environmental exposure has a role in lung cancer and COPD development and exacerbation needs further research.

BACKGROUND Indoor air pollution emitted by smoky coal combustion in unventilated fire pits used to cause high lung cancer mortality in Xuanwei. Stove improvements were implemented from the 1970s to the 1980s. However, the present lung cancer mortality rate in Xuanwei shows almost no significant declining trend. Tobacco use is another established risk factor for lung cancer. Smoking prevalence and secondhand smoke (SHS) exposure rate are both high in Xuanwei. Therefore, in this study we evaluated the relationship among indoor air pollution over 30 years ago, tobacco use, and lung cancer risk, to further explore the competitive effects of these two risk factors. METHODS A case-control study design was used. We constructed an unconditional logistic regression model to evaluate the relationship among indoor air pollution, tobacco use, and lung cancer risk, adjusting the covariates and with an interactive term between the two key variables. We further quantitatively assessed the maximum decrease in the indoor air pollution effect when facing competition from tobacco use via a sensitivity analysis. First, the effect of indoor air pollution on lung cancer without considering tobacco use was estimated. Then, we calculated a "bias factor" and divided the effect estimation by this factor. RESULTS We found a strong delayed effect of indoor air pollution over 30 years ago in each subgroup with different tobacco use history. The effects of tobacco use were relatively small, but in areas without smoky coal combustion and indoor air pollution over 30 years prior, the lung cancer risk caused by tobacco use became much stronger and statistically significant. Moreover, we assessed that the effects of tobacco use on lung cancer could reduce a maximum of 18%-30% of the effects of indoor air pollution, but did not influence their statistical significance; the competitive effect from ever smoking was stronger than that from SHS exposure. CONCLUSIONS At present in Xuanwei, delayed effect of the indoor air pollution over 30 years ago remains the major risk factor for lung cancer. Concomitantly, the adverse effect of tobacco use on lung cancer is becoming more apparent; local governments should start considering public health activities for smoking cessation promotion and SHS exposure prevention.

Background Inherited susceptibility and environmental carcinogens are crucial players in lung cancer etiology, and both exhibit population heterogeneity. MUC16 is overexpressed in various cancers and often associated with poor prognosis. Present work was to investigate the clinical significance of MUC16 in non-small cell lung cancer patients affected by familial lung cancer (FLC) and indoor air pollution caused by coal use. Methods Clinicopathologic characteristics and MUC16 expression were analyzed and evaluated in our subject population. Vectors were constructed for MUC16 gene knockout and overexpression, then we examined how MUC16 affected lung cancer cell behaviors, including proliferation, migration, invasion and chemoresistance. Results FLC showed significant association with early-onset (P<0.01) and later stage (P<0.01). Indoor air pollution was associated with younger age (P<0.01), later stage (P<0.05) and AD histology type (P<0.05). Interestingly, two age peaks were observed in our FLC and sporadic group respectively, possibly suggesting multiple major contributors to lung cancer in our subject population. MUC16 overexpression was significantly associated with FLC (P<0.05), indoor air pollution (P<0.01) and later stage (P<0.01), additionally more metastasis cases were observed in patients with up-regulated MUC16 (18.1% vs. 10.3%). Taken together, elevated MUC16 may potentially be one molecular character of FLC in local residents. Intriguingly, patients with more MUC16 up-regulation seemed to have a lower number of white blood cells, especially neutrophils, this reflected MUC16's role in immune regulation. In cell behavior experiments, high MUC16 level could contribute to lung cancer cell proliferation, migration, invasion and chemoresistance, but there were variations among cell lines. Conclusions MUC16 plays crucial roles in lung cancer pathogenesis, progression and chemoresistance. Interestingly, its association with FLC and indoor air pollution highlights the complexity of lung cancer etiology. Our findings provide useful information to study the intricate interaction between environmental carcinogens and population genetic background.

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Researchers have uncovered a potential mechanism underlying the known link between air pollution and lung cancer in never smokers. Their findings suggest that normal cells with aging-related mutations may be susceptible to tumorigenic reprogramming if regularly exposed to fine particles, namely PM2.5.

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Cancer is a major life risk disease in the world. One of the main causes of cancer diseases is smoking and chewing tobacco products which are the principal risk factor for causation of lung cancer for males. Air pollution is a complex mixture of particulate matter and gases produced by industrial and commercial activities and different types of transportations. But according to the WHO, particulate matter Trusted Source is most closely associated with cancer. Particulate matter refers to a mix of tiny solid and liquid particles that are suspended in the air. We shall conclude that our analysis suggested the existence of the long term effects of air pollution of common levels on lung cancer. In the Chennai regions, higher air pollution associated with increase transmission of lung cancer. Also, air pollution factors NOX, SO2 , PM2.5 and PM10 in Chennai district were taken into account of this research study. The data were analyzed with Poisson regression analysis using R software. The aim of this study is to estimate the associations between air pollution and lung cancer in Chennai district, Tamil Nadu.

The domestic combustion of locally sourced smoky (bituminous) coal in Xuanwei and Fuyuan counties, China, is responsible for some of the highest lung cancer rates in the world. Recent research has pointed to methylated PAHs (mPAHs), particularly 5-methylchrysene (5MC), within coal combustion products as a driving factor. Here we describe measurements of mPAHs in Xuanwei and Fuyuan derived from controlled burnings (i.e., water boiling tests, WBT, n = 27) representing exposures during stove use, and an exposure assessment (EA) study (n=116) representing 24 h weighted exposures. Using smoky coal leads to significantly higher concentrations of known and likely human carcinogens than using smokeless coal, including 5MC (3.7 ng/m3 vs. 1.0 ng/m3 for EA samples and 100.8 ng/m3 vs. 2.2 ng/m3 for WBT samples), benzo[a]pyrene (38.0 ng/m3 vs. 7.9 ng/m3 for EA samples and 455.3 ng/m3 vs. 12.0 ng/m3 for WBT samples), and 7,12-dimethylbenz[a]anthracene (1.9 ng/m3 vs. 0.2 ng/m3 for EA samples and 47.7 ng/m3 vs. 0.6 ng/m3 for WBT samples). Mixed effect models for both EA samples and WBT samples revealed clear variation in mPAHs concentrations depending on smoky coal source while stove ventilation was consistently found to reduce measured concentrations (by up to nine fold and 65 fold for EA and WBT samples respectively when using smoky coal). Fuel type had a larger influence on mPAHs concentrations than stove type. These findings indicate that users of smoky coal experience exposure to many PAHs, including known and suspected human carcinogens (especially during cooking activities), many of which are not routinely tested for. Collectively, this provides insights into the potential etiologies of lung cancer in the region and further highlights the importance of clean fuel transitions and stove refinements as the final goal for reducing household air pollution and its associated health risks.

More than 50% of women worldwide are exposed to Environmental Tobacco Smoke (ETS). The impact of ETS on lung cancer remains unclear. Cohort studies since the late 1990s have provided new evidence of female lung cancer risk due to ETS. The objective of this meta-analysis and systematic review was to analyze the association of ETS with female lung cancer risk from 1997 to 2017, organised based on research design. According to our applied inclusion and exclusion criteria, 41 published studies were included. The relative risk (RR) from the cohort studies or odds ratio (OR) from case-control studies were extracted to calculate the pooled risks based on the type of study. The summary risks of ETS were further explored with the modulators of ETS exposure sources and doses. The pooled risks of lung cancer in non-smoking women exposed to ETS were 1.35 (95% CI: 1.17–1.56), 1.17 (95% CI: 0.94–1.44), and 1.33 (95% CI: 1.17–1.51) for case-control studies, cohort studies, and both types of studies, respectively. The summary RR estimate of the cohort studies was not statistically significant, but the RR increased with increasing doses of ETS exposure (p trend < 0.05). Based on the results of this study, ETS might be an important risk factor of female lung cancer in non-smokers.

Background: To investigate the association between exposure to environmental tobacco smoke (EVT) and the incidence of lung cancer (LC) in nonsmoking adults. Method: PubMed, Cochrane, Embase, Wanfang, CNKI, and VIP database were searched by the index words to identify the qualified case-control studies, and relevant literature sources were also searched. The latest research was done in June 2017. Odds radio (OR) along with 95% confidence interval (95% CI) were used to analyze the main outcomes. Result: Twenty RCTs were involved in the meta-analysis with 13,004 adults in the case group and 11,199 adults in the control group. The results indicated that compared with the nonexposure population, the risk of LC incidence was significantly higher in EVT exposure (OR: 1.64, 95% CI: 1.34–2.01), EVT male exposure (OR: 1.62, 95% CI: 1.16–2.28), EVT female exposure (OR: 1.57, 95% CI: 1.43–1.72), EVT exposure at workplace (OR: 1.78, 95% CI: 1.29–2.44), EVT exposure at home (OR: 1.53, 95% CI: 1.01–2.33), and EVT female exposure at home (OR: 1.55, 95% CI: 1.34–1.79). However, there is still no significant difference among the risk of LC incidence in EVT male exposure at workplace (OR: 1.51, 95% CI: 0.74–3.06), EVT female exposure at workplace (OR: 1.23, 95% CI: 0.99–1.53), and EVT male exposure at home (OR: 1.24, 95% CI: 0.68–2.26). Conclusion: EVT exposure is prospectively associated with a significantly increased risk of LC incidence. More high quality studies are required to address the association between EVT exposure and LC incidence.

Objective: To assess the association between long-term exposures to smoky coal, environmental tobacco smoke (ETS) and lung cancer incidence in China. Methods: A meta-analysis was performed on literature searched through Web of Science, Chinese National Knowledge Infrastructure, Weipu, and Wanfang databases. Odds ratio (OR) with 95% confidence intervals (CIs) was used to assess the strength of association between air pollution and lung cancer in China. Results: Twenty-eight studies were included in the meta-analysis. Stratification by ETS exposure source, amount, and gender found a variation in effect. The pooled OR (95% CI) for exposure to spousal, parents, and work ETS was 1.153 (1.000–1.329), 2.117 (1.626–2.755), and 1.454 (1.307–1.618), respectively. The OR (95% CI) values related to childhood exposure was 1.297 (1.142–1.473), adulthood exposure 1.102 (0.937–1.296), exposure lower than 20 cigarette/day 1.088 (0.809–1.464), higher than 20 cigarette/day 1.776 (1.392–2.267), male 1.555 (1.304–1.855), female 1.487 (1.265–1.748), and coal use 1.490 (1.330–1.669). Conclusion: The meta-analysis provided evidence that indoor coal use and ETS were significantly associated with lung cancer in China.

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Malignant neoplasms are among the most common diseases and are responsible for the majority of deaths in the developed world. In contrast to men, available data show a clear upward trend in the incidence of lung cancer in women, making it almost as prevalent as breast cancer. Women might be more susceptible to the carcinogenic effect of tobacco smoke than men. Furthermore, available data indicate a much more frequent mutation of the tumor suppressor gene-p53 in non-small cell lung cancer (NSCLC) female patients compared to males. Another important factor, however, might lie in the female sex hormones, whose mitogenic or carcinogenic effect is well known. Epidemiologic data show a correlation between hormone replacement therapy (HRT) or oral contraceptives (OCs), and increased mortality rates due to the increased incidence of malignant tumors, including lung cancer. Interestingly, two types of estrogen receptors have been detected in lung cancer cells: ERα and ERβ. The presence of ERα has been detected in tissues and non-small-cell lung carcinoma (NSCLC) cell lines. In contrast, overexpression of ERβ is a prognostic marker in NSCLC. Herein, we summarize the current knowledge on the role of estrogens in the etiopathogenesis of lung cancer, as well as biological, hormonal and genetic sex-related differences in this neoplasm.

Lung cancer is the second most common cancer in the world, accounting for 11.4% of all cancers, but with 18.0% of total cancerrelated deaths, it is the leading cause of cancer death.1 In Australasia, the incidence of lung cancer varies between 19.1 and 42.1 per 100 000 population, with the strongest risk factors historically being increasing age and tobacco smoke exposure.2,3 However, the proportion of (predominantly) female never smokers with lung cancer is increasing in many countries, particularly across SouthEast Asia, together with an enlarging proportion of adenocarcinomas and molecular mutations, especially of the epidermal growth factor receptor (EGFR).2,4 Lung cancer in never smokers is increasingly being recognised as biologically distinct from smokingrelated lung cancers, although there is overlap with other risk factors such as environmental and genetic interactions, biofuel and occupational exposures, and indoor and outdoor pollution.2,4 The incidence of lung cancer in several developed countries (eg, the United Kingdom and the United States) has started to fall. However, despite a projected fall in agestandardised lung cancer rates in Australia over the next two decades, the number of deaths from lung cancer is expected to continue to increase due to population growth and ageing.2,5

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Recent genome-wide association studies (GWASs) have identified 15q25.1 as a lung cancer susceptibility locus. Here, we sought to explore the direct carcinogenic effects of genetic variants in this region on the risk of developing lung adenocarcinoma (ADC). Five common SNPs (rs8034191, rs16969968, rs1051730, rs938682, and rs8042374) spanning the 15q25.1 locus were assayed in a case-control study examining a cohort of 301 lung ADCs and 318 healthy controls. Stratification analysis by gender, smoking status, and tumor, node, metastasis (TNM) classification, was performed. In addition, sections from ADC tissue and normal tissue adjacent to tumors were stained with an anti-CHRNA3 (cholinergic receptor nicotinic α3) antibody by immunohistochemistry in 81 cases. Our results demonstrate that rs8042374, a variant of the CHRNA3 gene, is associated with an increased risk of ADC with an OR of 1.76 (95% CI: 1.17–2.65, p = 0.024). This variant was linked to a greater risk of ADC in female nonsmokers (OR (95% CI): 1.81 (1.05–3.12), p = 0.032) and female stage I + II cases (OR (95% CI): 1.92 (1.03–3.57), p = 0.039). Although located within the same gene, rs938682 showed protective effects for smokers, stage III + IV cases, and male stage III + IV cases. Additionally, the CHRNA3 protein level in ADC tissue was slightly higher than in the surrounding normal lung tissue, based on immunohistochemical analysis. Our results suggest that the CHRNA3 polymorphism functions as a genetic modifier of the risk of developing lung ADC in the Chinese population, particularly in nonsmoking females.

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Lung cancer has traditionally been associated with advanced age; however, its increasing incidence among young adults raises concerning questions regarding its etiology and unique considerations for this population. In contrast to the older population, the onset of lung cancer at younger age may be attributed to a complex interplay of incompletely understood individual susceptibility and prevalent environmental risk factors beyond tobacco smoke exposure, such as radon gas and air pollution, which are widespread globally. Consequently, this leads to distinct clinical and molecular profiles, requiring a tailored approach. Furthermore, a diagnosis of cancer represents a threatening event during the prime years of a young person's life, prompting concern about career development, social aspects, fertility aspirations, and physical independence. This poses significant additional challenges for health care professionals in a field that remains underexplored. This comprehensive review recognizes lung cancer in young adults as a distinct entity, exploring its clinical and molecular characteristics, diverse predisposing factors, and priorities in terms of quality of life, with the aim of providing practical support to oncologists and enhancing our understanding of this under-researched population.

BACKGROUND unlike familial non polyposis colorectal cancer (Lynch syndrome) and familial breast cancer, no genes have been confidently associated with familial lung cancer with the exception of the EGFR and the TP53 genes. Germinal Pathogenetic Variants (GPV) in these two genes account for 0.34-0.9% and 0.8 % lung adenocarcinoma, respectively. OBJECTIVE the aim of this study was to identify rare genetic variants associated with higher risk of developing lung cancer. METHODS we performed exome sequencing in the germinal DNA of 16 patients who had a positive familial history of lung cancer: 14 patients had lung cancer at enrollment whereas 2 patients developed cancer during the course of the study.. Two families had two affected relatives (mother and daughter and two sisters). RESULTS we identified rare clinically significant variants and VUS (Variant of Unknown Significance) in five well known cancer genes (POLE, PDGFRA, RTEL1, HNF1A and MITF) in five patients. One patient carried three variants and was exposed to environmental risk factors as smoking and asbestos. Common suscetibility variants in known cancer genes were also identified. We also identified additional potentially clinically relevant rare variants in other genes not previously associated to lung cancer. These genes include HGS, NME4, HAPLN1, ATMIN, CEACAM, MPEG1, USP4, TP53BP2, ERAP1, TNFAIP8L3, CASP1, MCC, SERPINA3, VIRMA, FOXK2, DNAH8, RASA2, GLI3. CONCLUSIONS several lines of evidence suggest that these genes are of potential clinical impact in lung cancer even though they have not been correlated with lung cancer in the OMIM database or other genetic databases. Therefore, these genes deserve further investigations: segregation analysis, enlarged cohorts and in vitro/in vivo studies could help to clarify their role in lung cancer.

The association of Interleukin-18 (IL-18) genetic polymorphism with lung cancer risk has yielded inconsistent findings in previous studies. The current research aims to clarify the relationship of IL-18 gene polymorphism with lung cancer susceptibility through experimental investigation and meta-analysis, providing insights for lung cancer prevention and treatment. We conducted a thorough search of major databases from their inception until March 2024. OR and 95%CI were calculated to know the results of meta-analysis. The IL-18 gene polymorphism was detected using the PCR-RFLP method. Significant associations were detected across all genetic models in allele contrast (A vs. C: Odds Ratio [OR] = 1.29, 95% Confidence Interval [CI] = 1.07-1.55, p = 0.006), homozygote comparison (AA vs. CC: OR = 1.87, 95%CI = 1.34-2.62, p < 0.001), recessive genetic model (AA vs. CT/CC: OR = 1.54, 95%CI = 1.08-2.20, p = 0.018), and dominant genetic model (AA/AC vs. CC: OR = 1.41, 95%CI = 1.12-1.78, p = 0.003). Three genotypes (AA, AC, and CC) were identified for the IL-18 -607 C/A polymorphism, with significant associations noted for the AA genotype and A allele (p = 0.018 and 0.005, respectively). This is the first study which investigates this polymorphism with lung cancer in population of eastern China. The IL-18 -607 C/A polymorphism appears to significantly increase the risk of lung cancer in the population of Eastern China. Further research is imperative to validate these findings.

BACKGROUND Fine particulate matter (PM2.5), smoking, and genetic factors are associated with lung cancer. However, the relationship between PM2.5, smoking and subtypes of lung cancer remains unclear. Moreover, it is unclear whether genetic risk modifies the impact of PM2.5 and smoking on incident lung cancer. METHODS A total of 298,069 participants from the UK Biobank study without lung cancer at baseline were included in this study. Hazard ratios (HRs) with 95 % confidence intervals (CIs) were estimated using multivariable Cox proportional models for the association of lung cancer and its subtypes with PM2.5, smoking, and genetic risk. Potential gene-smoking or gene-PM2.5 interactions were also estimated. We further estimated population attributable fractions for incident lung cancer. RESULTS During 10.4 years of follow-up, 1683 incident lung cancer cases were identified. Our analysis found that genetic variants, smoking, and PM2.5 were significantly associated with incident lung cancer. For different histological types of lung cancer, the HRs for squamous cell lung carcinoma associated with PM2.5 (per 5 μg/m3 increment) and current smoking were 2.76 (95 % CI: 1.72, 4.42, p < 0.001) and 48.64 (95 % CI: 27.96, 84.61, p < 0.001), while the HRs for lung adenocarcinoma were 1.59 (95 % CI: 1.13, 2.23, p < 0.001) and 9.89 (95 % CI: 7.91, 12.36, p < 0.001), respectively. We further found that participants with high levels of PM2.5 pollution and high genetic risk had the highest risk of incident lung cancer (HR = 1.81, 95 % CI: 1.39, 2.35, p < 0.001), while the interaction between PM2.5 and genetic risk was not statistically significant. We observed that the population attributable fractions of lung cancer attributable to current smoking and high PM2.5 exposure were estimated to be 67.45 % and 17.59 %. CONCLUSION Genetic susceptibility, smoking, and PM2.5 are important risk factors for lung cancer. Both smoking and PM2.5 are more closely associated with an elevated risk of squamous cell lung cancer.

Although several lung cancer susceptibility loci have been identified, much of the heritability for lung cancer remains unexplained. Here 14,803 cases and 12,262 controls of European descent were genotyped on the OncoArray and combined with existing data for an aggregated genome-wide association study (GWAS) analysis of lung cancer in 29,266 cases and 56,450 controls. We identified 18 susceptibility loci achieving genome-wide significance, including 10 new loci. The new loci highlight the striking heterogeneity in genetic susceptibility across the histological subtypes of lung cancer, with four loci associated with lung cancer overall and six loci associated with lung adenocarcinoma. Gene expression quantitative trait locus (eQTL) analysis in 1,425 normal lung tissue samples highlights RNASET2, SECISBP2L and NRG1 as candidate genes. Other loci include genes such as a cholinergic nicotinic receptor, CHRNA2, and the telomere-related genes OFBC1 and RTEL1. Further exploration of the target genes will continue to provide new insights into the etiology of lung cancer.

Lung cancer is one of the most critical global health threats, as the second most common cancer and leading cause of cancer deaths globally. While smoking is the primary risk factor, an increasing number of cases occur in nonsmokers, with lung cancer in nonsmokers (LCNS) now recognized as the fifth leading cause of cancer mortality worldwide. Recent evidence identifies air pollution, particularly fine particulate matter (PM2.5), as a significant risk factor in LCNS. PM2.5 can increase oxidative stress and inflammation, induce genetic alterations and activation of oncogenes (including the epidermal growth factor receptor, EGFR), and contribute to lung cancer progression. This review summarizes the current understanding of how exposure to PM2.5 induces lung carcinogenesis and accelerates lung cancer development. It underscores the importance of prevention and early detection while calling for targeted therapies to combat the detrimental effects of air pollution. An integrated approach that combines research, public health policy, and clinical practice is essential to reduce the lung cancer burden and improve outcomes for those affected by PM2.5 exposurrre. In this review, PC Yang and colleagues discuss the role of air pollution, particularly the fine particulate matter PM2.5, in lung carcinogenesis.

Alternative polyadenylation (APA) plays a crucial role in cancer development and prognosis. However, the molecular characteristics of APA related to non-small cell lung cancer (NSCLC) susceptibility remain understudied especially in East Asian populations. In this study, we constructed an atlas of APA-regulated 3' untranslated region (3'UTR) and profiled its genetic regulation in 747 lung tissue samples (including tumors and paired normal tissues) from 417 Chinese NSCLC patients. We verified a significant global shortening of 3'UTRs in tumor samples compared to normal samples and underscored the value of APA-regulation as prognostic markers. The 3'UTR APA quantitative trait loci (3'aQTL) was identified by regressing the percentage of distal poly(A) site usage index (PDUI) value on genetic variants. We found that a significant proportion 3'aQTL are independent of genetic regulation of expression and are specific in Chinese. We also conducted a 3'UTR APA transcriptome-wide association study (3'aTWAS) by integrating the APA regulation atlas with a genome-wide association studies (GWAS) for NSCLC involving 7, 035 cases and 185, 413 cancer-free controls. We identified NSCLC-associated genes. Combining the consistent results from colocalization analysis, differential APA analysis, and survival analysis, we provide novel evidence for the role APA regulation in NSCLC and identified potential upstream regulators. Overall, our study profiled the APA regulation and highlighted the substantial role of APA in NSCLC carcinogenesis and prognosis. Xiaohang Xu, Sicong Wang, Hanyi Zhou, Qilong Tan, Zeyong Lang, Yun Zhu, Huadi Yuan, Zixiang Wu, Ling Zhu, Kejia Hu, Wenyuan Li, Dan Zhou, Ming Wu, Xifeng Wu. Transcriptome-Wide Association Study of Alternative Polyadenylation Identifies Susceptibility Genes in Non-Small Cell Lung Cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 4064.

OBJECTIVES Lung Cancer (LC) is a multifactorial disease for which the role of genetic susceptibility has become increasingly relevant. Our aim was to use artificial intelligence (AI) to analyze differences between patients with LC based on family history of cancer (FHC). MATERIALS AND METHODS From August 2016 to June 2020 clinical information was obtained from Thoracic Tumors Registry (TTR), a nationwide database sponsored by the Spanish Lung Cancer Group. In addition to descriptive statistical analysis, an AI-assisted analysis was performed. The German Technical Information Library supported the merging of data from the electronic medical records and database of the TTR. The results of the AI-assisted analysis were reported using Knowledge Graph, Unified Schema and descriptive and predictive analyses. RESULTS Analyses were performed in two phases: first, conventional statistical analysis including 11,684 patients of those 5,806 had FHC. Median overall survival (OS) for the global population was 23 months (CI 95 %: 21.39-24.61) in patients with FHC versus 21 months (CI 95 %: 19.53-22.48) in patients without FHC (NFHC), p < 0.001. The second AI-assisted analysis included 5,788 patients of those 939 had FHC. 58.48 % of women with FHC had LC. 9.53 % of patients had an EGFR or HER2 mutation or ALK translocation and at least one relative with cancer. A family history of LC was associated with an increased risk of smoking-related LC. Non-smokers with a family history of LC were more likely to have an EGFR mutation in NSCLC. In Bayesian network analysis, 55 % of patients with a family history of LC and never-smokers had an EGFR mutation. CONCLUSION In our population, the incidence of LC in patients with a FHC is higher in women and younger patients. FHC is a risk factor and predictor of LC development, especially in people ≤ 50 years. These results were confirmed by conventional statistics and AI-assisted analysis.

Introduction: Inherited genetic determinants of lung cancer risk remain relatively elusive. Germline mutations in EGFR and erb‐b2 receptor tyrosine kinase 2 (ERBB2) have been previously reported in lung cancers that may be associated with genetic susceptibility to lung cancer. Methods: We retrospectively analyzed a cohort of 12,833 Chinese lung cancer patients tested by targeted next‐generation sequencing. Patients with EGFR and ERBB2 germline mutations were identified, and their clinical information and family history were summarized. Growth factor independency of EGFR germline mutations was further analyzed in vitro. Results: Eight different heterozygous EGFR germline mutations from 14 adenocarcinoma patients (0.12%) were identified within or adjacent to the kinase domain, including K757R (n = 5), R831H (n = 2), D1014N (n = 2), G724S, V786M, T790M, L792F, and L844V. Only one patient harbored the ERBB2‐V1128I germline mutation. Five of 15 patients had family history of cancer. Notably, the patient with EGFR‐T790M germline mutation had multiple maternal family members diagnosed with lung cancers, strongly supporting its role in inherited lung cancer. Concurrent known somatic driver mutations were not detected in 5 patients at diagnosis, 1 of whom harbored the EGFR‐L844V germline mutation and showed superior response to afatinib. Consistently, EGFR‐K757R and L844V mutations were able to be interleukin 3 – independent in vitro and were sensitive to EGFR tyrosine kinase inhibitors. Conclusions: EGFR/ERBB2 germline mutations were found to be rare in Chinese lung cancer patients with more diversity other than the previously reported EGFR‐T790M, with EGFR‐K757R being the most common EGFR germline mutation. Patients with EGFR germline mutations without other known driver mutations might benefit from tyrosine kinase inhibitor treatment.

Incorporating susceptibility genetic variants of risk factors has been reported to enhance the risk prediction of polygenic risk score (PRS). However, it remains unclear whether this approach is effective for lung cancer. Hence, we aimed to construct a meta polygenic risk score (metaPRS) of lung cancer and assess its prediction of lung cancer risk and implication for risk stratification. Here, a total of 2180 genetic variants were used to develop nine PRSs for lung cancer, three PRSs for different histopathologic subtypes, and 17 PRSs for lung cancer‐related risk factors, respectively. These PRSs were then integrated into a metaPRS for lung cancer using the elastic‐net Cox regression model in the UK Biobank (N = 442,508). Furthermore, the predictive effects of the metaPRS were assessed in the prostate, lung, colorectal, and ovarian (PLCO) cancer screening trial (N = 108,665). The metaPRS was associated with lung cancer risk with a hazard ratio of 1.33 (95% confidence interval: 1.27–1.39) per standard deviation increased. The metaPRS showed the highest C‐index (0.580) compared with the previous nine PRSs (C‐index: 0.513–0.564) in PLCO. Besides, smokers in the intermediate risk group predicted by the clinical risk model (1.34%–1.51%) with the intermediate‐high genetic risk had a 6‐year average absolute lung cancer risk that exceeded the clinical risk model threshold (≥1.51%). The addition of metaPRS to the clinical risk model showed continuous net reclassification improvement (continuous NRI = 6.50%) in PLCO. These findings suggest the metaPRS can improve the predictive efficiency of lung cancer compared with the previous PRSs and refine risk stratification for lung cancer.

Metabolic dysregulation is recognized as a significant hallmark of cancer progression. Although numerous studies have linked specific metabolic pathways to cancer incidence, the causal relationship between blood metabolites and lung cancer risk remains unclear. Genomic data from 29,266 lung cancer patients and 56,450 control individuals from the Transdisciplinary Research in Cancer of the Lung and the International Lung Cancer Consortium (TRICL-ILCCO) were utilized, and findings were replicated using additional data from the FinnGen consortium. The analysis focused on the associations between 486 blood metabolites and the susceptibility to overall lung cancer and its three major clinical subtypes. Various Mendelian randomization methods, including inverse-variance weighting, weighted median estimation, and MR-Egger regression, were employed to ensure the robustness of our findings. A total of 19 blood metabolites were identified with significant associations with lung cancer risk. Specifically, oleate (OR per SD = 2.56, 95% CI: 1.51 to 4.36), 1-arachidonoylglyceropholine (OR = 1.79, 95% CI: 1.22 to 2.65), and arachidonate (OR = 1.67, 95% CI: 1.16 to 2.40) were associated with a higher risk of lung cancer. Conversely, 1-linoleoylglycerophosphoethanolamine (OR = 0.57, 95% CI: 0.40 to 0.82), ADpSGEGDFXAEGGGVR, a fibrinogen cleavage peptide (OR = 0.60, 95% CI: 0.47 to 0.77), and isovalerylcarnitine (OR = 0.62, 95% CI: 0.49 to 0.78) were associated with a lower risk of lung cancer. Notably, isoleucine (OR = 9.64, 95% CI: 2.55 to 36.38) was associated with a significantly higher risk of lung squamous cell cancer, while acetyl phosphate (OR = 0.11, 95% CI: 0.01 to 0.89) was associated with a significantly lower risk of small cell lung cancer. This study reveals the complex relationships between specific blood metabolites and lung cancer risk, highlighting their potential as biomarkers for lung cancer prevention, screening, and treatment. The findings not only deepen our understanding of the metabolic mechanisms of lung cancer but also provide new insights for future treatment strategies.

Lung cancer is one of the most prevalent and deadly forms of cancer worldwide. Whilst smoking is the main determinant, genetic factors also play a crucial role as genome-wide association studies (GWAS) have identified >50 loci associated with lung cancer risk. Yet, for most of these loci, it is still unknown how they contribute to lung cancer risk. Expression quantitative trait loci (eQTL) studies have been powerful in linking GWAS variants to potential target genes, providing genetic mechanisms underlying common diseases such as cancers. However, the current eQTL resources lack ancestral diversity and are primarily based on bulk tissues. Emerging single-cell eQTL (sc-eQTL) approaches can detect context-specific gene regulation but are mainly of blood samples or cultured cells and still representing European populations. This limits our abilities to test GWAS variants in cancer-relevant cell types as well as in diverse populations. To generate a resource to characterize lung cancer GWAS loci, we are building a lung sc-eQTL dataset of Asian population while addressing common challenges of tissue sc-eQTL. Namely, processing fresh tissue in a population scale is logistically challenging and costly, and epithelial cells (including cell types of lung cancer origin) are vulnerable to the dissociation and freezing/thawing process. To address these issues, we incorporated sample multiplexing and cell type balancing. We collected fresh tumor-distant normal lung tissues from 131 never-smoking Korean women and dissociated them before cryopreservation. We then performed single-cell RNA sequencing (scRNA-seq) using 10x Chromium Single Cell 3’ v3.1 chemistry with multiplexing of ~6 samples/batch. To enrich for epithelial cells, we utilized flow cytometry with surface markers of four major lung cell types (epithelial: EpCAM+/CD45-, immune: EpCAM-/CD45+, endothelial and stromal: EpCAM-/CD45-) before 10X library preparation. Concurrently, we performed DNA genotyping and imputation using matched blood samples. Following scRNA-seq (~36,000 reads/cell) we performed a genotype-based sample demultiplexing using Demuxlet. By integrating Demuxlet and Scrublet, we identified ~89% of the detected cells as singlets. After applying QC to filter empty droplets and low-quality cells, we obtained 428,619 cells or 3,272 cells/patient. Cell annotation guided by Azimuth label transfer using the Human Lung Cell Atlas, identified 28 cell types including 7 of epithelial origins. We will further perform eQTL analyses for individual cell types using pseudo-bulk and LIMIX (linear mixed model) or SAIGE-qtl (poisson regression) methods followed by aggregation across the cell types. By incorporating lung cancer GWAS data, we will identify cell-type specific susceptibility genes. Our dataset will provide a unique resource for lung cancer research. Citation Format: Thong Luong, Erping Long, Jinhu Yin, Bolun Li, Ju Hye Shin, Elelta Sisay, Alexander Kane, Alyxandra Golden, Yoon Soo Chang, Nicholas Banovich, Nathaniel Rothman, Jinyoung Byun, Qing Lan, Christopher Amos, Jianxin Shi, Jin Gu Lee, Eun Young Kim, Jiyeon Choi. Establishing a single-cell eQTL dataset of lung tissues from Asian never-smokers to identify cell-type specific lung cancer susceptibility genes [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7331.

We investigated whether genetic susceptibility to tuberculosis (TB) influences lung adenocarcinoma development among never-smokers using TB genome-wide association study (GWAS) results within the Female Lung Cancer Consortium in Asia. Pathway analysis with the adaptive rank truncated product method was used to assess the association between a TB-related gene-set and lung adenocarcinoma using GWAS data from 5512 lung adenocarcinoma cases and 6277 controls. The gene-set consisted of 31 genes containing known/suggestive associations with genetic variants from previous TB-GWAS. Subsequently, we followed-up with Mendelian Randomization to evaluate the association between TB and lung adenocarcinoma using three genome-wide significant variants from previous TB-GWAS in East Asians. The TB-related gene-set was associated with lung adenocarcinoma (p = 0.016). Additionally, the Mendelian Randomization showed an association between TB and lung adenocarcinoma (OR = 1.31, 95% CI: 1.03, 1.66, p = 0.027). Our findings support TB as a causal risk factor for lung cancer development among never-smoking Asian women.

We assessed the association between a genome-wide polygenic risk score (PRS) developed for lung adenocarcinoma (LUAD) risk and mutation on the epidermal growth factor receptor (EGFR) gene in 998 East Asian never-smoking female LUAD cases (518 EGFR-positive; 480 EGFR-negative) and 4,544 never-smoking controls using case-case and multinomial regression analyses. We found that the PRS was more strongly associated with EGFR-positive LUAD compared to EGFR-negative LUAD, where the association between the fourth quartile of the PRS and EGFR-positive LUAD (OR=8.63, 95% CI:5.67, 13.14) was significantly higher than the association between the fourth quartile of the PRS with EGFR-negative LUAD (OR=3.50, 95% CI: 2.44, 5.00) (p-heterogeneity=3.66x10-3). Our findings suggest that germline genetic susceptibility may be differentially associated with LUAD in never-smoking female East Asian patients depending on the cancer's mutation status, which may have important public health and clinical implications.

Background: Lung cancer is the leading cause of cancer mortality worldwide, and incidence rates for the disease in never-smokers is among the highest in East Asian (EAS) women. Epidermal growth factor receptor (EGFR) is a transmembrane protein that regulates cellular proliferation and apoptosis, and mutations in the EGFR gene have been found to be a defining hallmark of lung adenocarcinoma (LUAD). We investigated if overall genetic susceptibility to LUAD, defined as a polygenic risk score (PRS), is differentially associated with LUAD by EGFR mutation status. Methods: The study consists of 998 female never-smoking histologically confirmed LUAD cases with data on EGFR mutation status and 4,544 female never-smoking controls from the Female Lung Cancer Consortium in Asia. Germline DNA samples were genotyped using the 370K, 610Q, or 660W microarrays. Genomic DNA extracted from fresh, frozen or formalin-fixed paraffin-embedded tumor tissue samples of LUAD cases were genotyped for EGFR mutations on exons 19 and 21. We defined cases with EGFR mutation on either exon as EGFR+ (n=518) and cases without such EGFR mutation as EGFR- (n=480). Weights from 942,592 single nucleotide variants derived from a previously conducted genome-wide association study were used in a Bayesian-based approach, LDpred2, to derive a PRS for all participants. We estimated the odds ratios (OR) and 95% confidence intervals (CI) for the association between continuous PRS, PRS quartiles and tumor EGFR mutation status using logistic regression models in a case-case analysis, as well as using a multinomial logistic regression treating controls as the reference. All models were adjusted for age, study and the top 10 principal components. Results: In case-case comparisons, compared to EGFR- LUAD, we found a positive association between continuous PRS and risk of EGFR+ LUAD (OR=1.17, 95% CI: 1.02, 1.34), as well as a dose-response relationship between quartiles of the PRS and EGFR+ LUAD (p-trend=0.003). We further found that the association between the fourth quartile of the PRS with EGFR+ LUAD (OR=8.63, 95% CI: 5.67, 13.14) was significantly higher than the association between the fourth quartile of the PRS with EGFR- LUAD (OR=3.50, 95% CI: 2.44, 5.00) compared to controls (p-heterogeneity=0.004). Conclusions: We found that the PRS developed for LUAD in EAS individuals was more strongly associated with EGFR+ LUAD compared to EGFR- LUAD, suggesting that germline genetic susceptibility may be differentially associated with LUAD in never-smoking female EAS patients depending on the cancer’s mutation status. Given that patients with LUAD respond differently to treatments that are used as targeted therapy depending on their EGFR mutation status, our findings may have important public health and clinical implications, which may guide risk stratification, screening, and treatment. Citation Format: Batel Blechter, Chao Agnes Hsiung, Keitaro Matsuo, Kouya Shiraishi, Kevin Wang, Haoyu Zhang, Wei Jie Seow, Jianxin Shi, Nilanjan Chatterjee, Jason Y.Y. Wong, Juncheng Dai, H. Dean Hosgood, I-Shou Chang, Jiyeon Choi, Wei Hu, Wei Zheng, Young Tae Kim, Xiao-Ou Shu, Qiuyin Cai, Pan-Chyr Yang, Dongxin Lin, Kexin Chen, Yi-Long Wu, Hongbin Shen, Takashi Kohno, Stephen J. Chanock, Nathaniel Rothman, Qing Lan. Polygenic risk score and lung adenocarcinoma risk among never-smokers by EGFR mutation status [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6149.

No abstract available

Background Characteristics of ground-glass nodules (GGNs) in Asian women who have never smoked with family history of lung cancer (FHLC) remain unexamined. Purpose To investigate the differences in GGN progression to lung cancer at low-dose CT (LDCT) screening between Asian women who have never smoked with and without FHLC, and to examine associations between FHLC and GGN prevalence and growth. Materials and Methods This single-center retrospective study included East Asian women who had never smoked and had no personal history of lung cancer who underwent baseline LDCT for a health checkup between January 2011 and December 2015. Radiologists reviewed GGNs at baseline and follow-up, using Fleischner Society guidelines. Prevalence of persistent, multiple, and growing GGNs and incidence of pathology-confirmed lung cancer were compared in patients with and without FHLC. Multivariable logistic and Cox regression analyses were used to explore associations between FHLC and GGN prevalence and growth, adjusting for total size and solid proportion of baseline GGNs. Results Of 10 151 patients (mean age, 54 years ± 10 [SD]), 694 (6.8%) reported FHLC and 9457 (93.2%) did not. Among all patients, 515 (5.1%) had persistent GGNs (median follow-up period, 2551 days [IQR, 1104-3458 days]), 199 (2.0%) had multiple GGNs, 49 (0.5%) experienced GGN growth, and 31 (0.3%) were diagnosed with lung cancer. Patients with FHLC had a higher prevalence of persistent GGNs (8.2% [57 of 694] vs 4.8% [458 of 9457]; P < .001), multiple GGNs (3.7% [26 of 694] vs 1.8% [173 of 9457]; P < .001), and growing GGNs (1.3% [nine of 694] vs 0.4% [40 of 9457]; P = .001) and higher lung cancer incidence (0.9% [six of 694] vs 0.3% [25 of 9457]; P = .006). In multivariable analysis, FHLC was associated with increased prevalence of persistent GGNs (odds ratio [OR], 1.69 [95% CI: 1.26, 2.26]; P < .001) and multiple GGNs (OR, 2.02 [95% CI: 1.32, 3.08]; P = .001). FHLC was an independent risk factor for GGN growth over a 10-year period (hazard ratio, 2.14 [95% CI: 1.03, 4.44]; P = .04) after adjustments. Conclusion In East Asian women who had never smoked and who underwent LDCT screening, FHLC was associated with an increased prevalence of persistent and multiple GGNs, including proven adenocarcinomas, and was an independent risk factor for GGN growth over a 10-year period. © RSNA, 2024 Supplemental material is available for this article. See also the editorial by Chang in this issue.

Although genome-wide association studies (GWASs) have identified some risk single-nucleotide polymorphisms in East Asian never-smoking females, the unexplained missing heritability is still required to be investigated. Runs of homozygosity (ROHs) are thought to be a type of genetic variation acting on human complex traits and diseases. We detected ROHs in 8,881 East Asian never-smoking women. The summed ROHs were used to fit a logistic regression model which noteworthily revealed a significant association between ROHs and the decreased risk of lung cancer (P < 0.05). We identified 4 common ROHs regions located at 2p22.1, which were significantly associated with decreased risk of lung cancer (P = 2.00 × 10-4 - 1.35 × 10-4). Functional annotation was conducted to investigate the regulatory function of ROHs. The common ROHs were overlapped with potential regulatory elements, such as active epigenome elements and chromatin states in lung-derived cell lines. SOS1 and ARHGEF33 were significantly up-regulated as the putative target genes of the identified ROHs in lung cancer samples according to the analysis of differently expressed genes. Our results suggest that ROHs could act as recessive contributing factors and regulatory elements to influence the risk of lung cancer in never-smoking East Asian females.

There has been a consistent rise in the incidence of non-small cell lung cancer (NSCLC) among individuals who have never smoked. Remarkably, over 50% of diagnosed female cases and 15-20% of male cases are never-smokers. Notably, NSCLC in never-smokers exhibits distinctive clinical and pathological features, notably a higher incidence of tumors with EGFR mutations, setting it apart from its counterpart in smokers. Despite the improved disease-free survival observed with EGFR-tyrosine kinase inhibitors, eventual relapse and limited responsiveness to immunotherapy are common, underscoring the urgency to comprehend the molecular mechanisms driving the escalating prevalence of NSCLC in never-smokers and develop targeted preventive and interceptive therapeutic strategies. The preponderance of females among NSCLC patients who never smoked has prompted an exploration into the potential contribution of estrogen to lung tumorigenesis. In contrast to prevailing research focused on estrogen receptor-mediated signaling, our investigations have yielded compelling evidence supporting the involvement of estrogen metabolism in lung carcinogenesis among never-smokers. This group is the first to report that estrogen is metabolized extensively in both mouse and human lungs, resulting in the generation of various derivatives, including the potential carcinogen 4-hydroxyestrogen (4-OHE). Notably, recent findings from our laboratory indicate that prolonged exposure of nonneoplastic human bronchial epithelial cells to 17β estradiol or 4-OHE, at concentrations approximating physiological levels, induces the accumulation of double-strand DNA breaks and cellular transformation. A comprehensive analysis was performed to further elucidate the mechanisms underlying the transformation process. Isolated transformed clones obtained after 9, 18, and 22 wks of exposure to 4-OHE were subjected to karyotyping, F.I.S.H., and RNA and exome sequencing. A longitudinal progression of aberrant chromosomal rearrangements and copy number alterations was observed, that increased with time of 4-OHE exposure. In addition, RNA-Seq analyses revealed the epithelial-mesenchymal transition pathway was highly enriched at the early timepoint (9 wks), while replicative stress-related signaling pathways were induced at all timepoints. To determine if the differentially expressed genes were also dysregulated in clinical lung cancer cases, TCGA lung adenocarcinoma (LUAD) data were examined. Interestingly, many of the genes upregulated after estrogen exposure were similarly overexpressed in the LUAD samples and often associated with a worse prognosis. In conclusion, our data support the role of estrogen metabolites in promoting lung cancer among never-smokers. (Supported by CA217161 and generous contributions from the Hellendall Family Foundation, Gregory G. Lawton and the Timothy and Aurora Hughes Cancer Research Fund.) Citation Format: Mitchell Cheung, Lisa A. Vanderveer, Daniel Krzizike, J. Nicholas Bodor, Joseph Treat, Joseph R. Testa, Margie L. Clapper. Contribution of estrogen metabolites to never-smoking lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1467.

BACKGROUND Whether female being more susceptible to lung cancer among never smokers (LCNS) than males has been a long-standing debate. METHOD A total of 26,339 married heterosexual couples included in this cohort study. Truncated (40-89) age-standardized incidence rates and incidence rate ratio (IRR) of lung cancer were calculated and compared between the two sexes. Cox regression models were used to estimate hazard ratio (HR) for evaluating sex differences in lung cancer risk. RESULTS In this large couples cohort study the prevalence of ever smoking was 2.1 % in wives and 65.4 % in husbands. Over a median follow-up of 12.5 years, incident lung cancer was documented in 293 wives and 500 husbands. The truncated age-standardized incidence rate per 100,000 person-years in all couples was significantly lower in wives (56.1) than their husbands (117.4), with an IRR of 0.48 for wives vs husbands. A similar pattern was observed among dual-smoker couples. However, the sex difference diminished when further adjusting for the duration and intensity of cigarette smoking. In contrast, among dual-nonsmoker couples, the corresponding age-standardized rate was significantly higher in wives (52.6) than their husbands (33.4), with an IRR of 1.57. Multivariable adjustment did not alter the result, with an HR for wives vs husbands of 1.54 (95 % CI, 1.05-2.27). CONCLUSIONS This study, for the first time, using a large cohort of married couples, demonstrates that females are more susceptible to LCNS than males.

BACKGROUND Although lung cancer incidence rates according to smoking status, sex, and detailed race/ethnicity have not been available, it is estimated that over half of Asian American, Native Hawaiian, and Pacific Islander (AANHPI) females with lung cancer have never smoked. METHODS We calculated age-adjusted incidence rates for lung cancer according to smoking status and detailed race/ethnicity among females, focusing on AANHPI ethnic groups, and assessed relative incidence across racial/ethnic groups. We used a large-scale dataset that integrates data from electronic health records from two large healthcare systems-Sutter Health in Northern California and Kaiser Permanente Hawai'i-linked to state cancer registries for incident lung cancer diagnoses between 2000-2013. The study population included 1,222,694 females (n = 244,147 AANHPI), 3,297 of which were diagnosed with lung cancer (n = 535 AANHPI). RESULTS Incidence of lung cancer among never-smoking AANHPI as an aggregate group was 17.1 per 100,000 (95% confidence interval [CI] = 14.9, 19.4), but varied widely across ethnic groups. Never-smoking Chinese American females had the highest rate (22.8 per 100,000, 95% CI = 17.3, 29.1). Except for Japanese American females, incidence among every never-smoking AANHPI female ethnic group was higher than that of never-smoking non-Hispanic White females, from 66% greater among Native Hawaiian females (incidence rate ratio = 1.66; 95% CI = 1.03, 2.56) to over 100% greater among Chinese American females (incidence rate ratio = 2.26; 95% CI = 1.67-3.02). CONCLUSIONS Our study revealed high rates of lung cancer among most never-smoking AANHPI female ethnic groups. Our approach illustrates the use of innovative data integration to dispel the myth that AANHPI females are at overall reduced risk of lung cancer and demonstrates the need to disaggregate this highly diverse population.

Abstract Background: Clinical, molecular, and genetic epidemiology studies displayed remarkable differences between ever- and never-smoking lung cancer. Methods: We conducted a stratified multi-population (European, East Asian, and African descent) association study on 44,823 ever-smokers and 20,074 never-smokers to identify novel variants that were missed in the non-stratified analysis. Functional analysis including expression quantitative trait loci (eQTL) colocalization and DNA damage assays, and annotation studies were conducted to evaluate the functional roles of the variants. We further evaluated the impact of smoking quantity on lung cancer risk for the variants associated with ever-smoking lung cancer. Results: Five novel independent loci, GABRA4, intergenic region 12q24.33, LRRC4C, LINC01088, and LCNL1 were identified with the association at two or three populations (P < 5 × 10−8). Further functional analysis provided multiple lines of evidence suggesting the variants affect lung cancer risk through excessive DNA damage (GABRA4) or cis-regulation of gene expression (LCNL1). The risk of variants from 12 independent regions, including the well-known CHRNA5, associated with ever-smoking lung cancer was evaluated for never-smokers, light-smokers (packyear ≤ 20), and moderate-to-heavy-smokers (packyear > 20). Different risk patterns were observed for the variants among the different groups by smoking behavior. Conclusions: We identified novel variants associated with lung cancer in only ever- or never-smoking groups that were missed by prior main-effect association studies. Impact: Our study highlights the genetic heterogeneity between ever- and never-smoking lung cancer and provides etiologic insights into the complicated genetic architecture of this deadly cancer.

Lung cancer is a leading cause of cancer mortality for most ethnic groups of Asian American females, including Chinese, Korean, Japanese, and Vietnamese Americans, a striking pattern given the exceedingly low prevalence of smoking among Asian American females in the general population. Recent research demonstrates that among Asian American females diagnosed with lung cancer, the vast majority of patients have never smoked, as high as > 80% among Chinese and Asian Indian American females. Despite declining rates in lung cancer overall in the United States, rates among Asian American females who have never smoked appear to be increasing. This Commentary articulates extant knowledge, based on studies in Asia, of a range of risk factors such as a family history of lung cancer, history of lung diseases including tuberculosis and chronic obstructive pulmonary diseases, exposure to cooking fumes and second-hand smoke, and various putative risk factors. Unique mutational profiles at the tumor level, including higher prevalence of EGFR mutations among Asian populations, highlight the importance of tumor genomic testing of newly-diagnosed patients. Additional research is essential, given the high burden of disease among Asian American females who have never smoked, and limited knowledge regarding contributing risk factors specific to Asian American females, as the risk factors identified in Asians living in Asia may not apply.

Lung cancer is the leading cause of cancer mortality among Chinese females despite the low smoking prevalence among this population. This study assessed the roles of reproductive factors in lung cancer development among Chinese female never-smokers. The prospective China Kadoorie Biobank (CKB) recruited over 0.5 million Chinese adults (0.3 million females) from 10 geographical areas in China in 2004–2008 when information on socio-demographic/lifestyle/environmental factors, physical measurements, medical history, and reproductive history collected through interviewer-administered questionnaires. Cox proportional hazard regression was used to estimate adjusted hazard ratios (HRs) of lung cancer by reproductive factors. Subgroup analyses by menopausal status, birth year, and geographical region were performed. During a median follow-up of 11 years, 2,284 incident lung cancers occurred among 282,558 female never-smokers. Ever oral contraceptive use was associated with a higher risk of lung cancer (HR = 1.16, 95% CI: 1.02–1.33) with a significant increasing trend associated with longer duration of use (p-trend = 0.03). Longer average breastfeeding duration per child was associated with a decreased risk (0.86, 0.78–0.95) for > 12 months compared with those who breastfed for 7–12 months. No statistically significant association was detected between other reproductive factors and lung cancer risk. Oral contraceptive use was associated with an increased risk of lung cancer in Chinese female never-smokers. Further studies are needed to assess lung cancer risk related to different types of oral contraceptives in similar populations.

Background/Aims Genome wide and candidate gene association studies have identified polymorphisms associated with the risk of lung cancer in never-smokers. This study was conducted to evaluate the association between 11 polymorphisms identified in female never smokers and the lung cancer risk in male smokers. Methods This study included 714 lung cancer patients and 626 healthy controls. The polymorphisms were genotyped using SEQUENOM MassARRAY iPLEX assay or Taq-Man assay. Results Two polymorphisms were associated with the risk of lung cancer in male smokers, as in female never smokers. Male smokers carrying the rs4975616 variant allele had a significantly decreased risk of lung cancer (in a codominant model: odds ratio, 0.77; 95% confidence interval, 0.61 to 0.96; p = 0.02). The rs9387478 polymorphism also reduced lung cancer risk in male smokers (in a codominant model: odds ratio, 0.85; 95% confidence interval, 0.73 to 0.997; p = 0.046). In a stratified analysis, the association between these polymorphisms and the risk of lung cancer was predominant in lighter smokers and for cases of adenocarcinoma. Conclusions These results suggest that a subset of polymorphisms known to be associated with the risk of lung cancer in female never smokers is also associated with the risk of lung cancer in male smokers.

BACKGROUND Lung cancer in never-smokers is an increasing issue, particularly in East Asia, where nonsmoking-related risk factors, such as genetic predispositions, play a crucial role. This study investigated the association of family history of lung cancer (FHLC) with lung cancer risk among never-smokers and identified when these risks increased. METHODS This prospective cohort study used data from the Kangbuk Samsung Cohort Study, which involved 357,322 Korean adults who underwent health screenings from 2011 to 2021. The 167,883 with a history of smoking or previous cancer diagnoses were excluded from this study. FHLC was evaluated through questionnaires, and incident lung cancer cases were determined through the Korea National Cancer Incidence Database. RESULTS Of the 189,439 study population, 11,678 reported FHLC. Incident lung cancer was observed in 25 (0.21%) participants with FHLC and 148 (0.083%) without FHLC, yielding an unadjusted hazard ratio (HR) of 1.76 (95% confidence interval [CI]: 1.15-2.69, P = .009). FHLC remained a significant risk factor after adjusting for sex, body mass index, alcohol consumption, exercise, and medical history (HR: 1.93, 95% CI: 1.24-3.01, P = .004). The risk of incident lung cancer based on FHLC significantly diverged after 45 years of age. Propensity score matching confirmed a higher lung cancer risk in nonsmokers with FHLC compared with those without FHLC. CONCLUSIONS Never-smokers with FHLC demonstrated a significantly higher risk of developing lung cancer, which risks start to increase after 45 years of age. Integrating FHLC into lung cancer screening models has the potential to enhance early detection.

Objectives Lung cancer is the leading cause of cancer mortality globally. Although often associated with smoking, up to 25% of cases worldwide and 50% in East Asia occur in “never-smokers.” There are currently no robust tools for predicting lung cancer in individuals who have never smoked (LCINS) for populations outside East Asia. Together with a group of patient representatives, the authors of this study aimed to summarise risk factors for LCINS and quantify risk in different geographical regions. Methods This study was prospectively registered (PROSPERO-CRD42022379253). The systematic review and meta-analysis included studies published from 2017 and aimed to comprehensively investigate risk factors associated with LCINS incidence. Risk of bias was assessed using Newcastle-Ottawa Scale. Results A total of 6725 reports were identified and 54 studies were included, with multivariable analysis of 192 factors in 16 million never-smokers. No studies were assessed as having high risk of bias. Of the participants, 8,241,269 (51.0%) were from Western countries. The meta-analysis found that female sex (adjusted hazard ratio [aHR] 1.28 [95% confidence interval or CI 1.12–1.47]), previous cancer (aHR 2.04 [1.95–2.13]), rheumatoid arthritis (aHR 1.41 [1.15–1.73]), passive smoking (aHR 1.30 [1.22–1.40]), PM10 (aHR 1.10 [1.09–1.11]), and PM2.5 (aHR 1.16 [1.03–1.30]) pollution were associated with LCINS. In planned subgroup analyses by region, LCINS was associated with family history of lung cancer in East Asian (aHR 1.56 [1.23–1.98]) but not Western countries (aHR 0.86 [0.35–2.11]). Conclusion We found key factors linked with LCINS, including female sex, rheumatoid arthritis, and pollution and, for the first time, quantified their association through meta-analyses of studies globally. This may be used to develop tools to detect LCINS earlier.

Long noncoding RNAs (lncRNAs) play important roles in the development of human cancers. This is the first case–control study of the association between specific polymorphisms in lncRNA genes and the risk of lung cancer, as well as the gene–environment interaction between the polymorphisms and cooking oil fume exposure in Chinese never-smoking females. A hospital-based case–control study was carried out in Shenyang, Liaoning province. The study included 395 cases and 556 controls. The polymorphisms of rs4785367, rs3803662, rs10750417, and rs1814343 in lncRNA genes were analyzed. The gene–environment interactions were explored on both additive and multiplicative scale. In addition, the results were listed as follows: for rs3803662, compared with the individuals carrying homozygous TT genotype, those with homozygous CC genotype had the decreased risk of lung cancer (adjusted odds ratio [OR] = 0.61, 95% confidence interval [CI] = 0.40–0.92, p = 0.018). As for rs4785367, compared with homozygous TT, homozygous CC could lessen the risk of lung cancer (adjusted OR = 0.54, 95% CI = 0.33–0.89, p = 0.016). The recessive models of rs3803662 and rs4785367 showed significant association (adjusted OR = 0.65, 95% CIs = 0.44–0.97, p = 0.033; adjusted OR = 0.54, 95% CIs = 0.33–0.88, p = 0.014). The C allele of rs3803662 was suggested to be protective allele of lung cancer (adjusted OR = 0.80, 95% CI = 0.66–0.97, p = 0.023). However, rs10750417 and rs1814343 polymorphisms were not significantly associated with lung cancer risks. The measures of additive interaction and logistic models suggested that the gene–environment interactions were not statistically significant on both additive and multiplicative scales.

Tobacco use is one of the main risk factors for Lung Cancer (LC) development. However, about 10–20% of those diagnosed with the disease are never-smokers. For Non-Small Cell Lung Cancer (NSCLC) there are clear differences in both the clinical presentation and the tumor genomic profiles between smokers and never-smokers. For example, the Lung Adenocarcinoma (LUAD) histological subtype in never-smokers is predominately found in young women of European, North American, and Asian descent. While the clinical presentation and tumor genomic profiles of smokers have been widely examined, never-smokers are usually underrepresented, especially those of a Latin American (LA) background. In this work, we characterize, for the first time, the difference in the genomic profiles between smokers and never-smokers LC patients from Chile. We conduct a comparison by smoking status in the frequencies of genomic alterations (GAs) including somatic mutations and structural variants (fusions) in a total of 10 clinically relevant genes, including the eight most common actionable genes for LC (EGFR, KRAS, ALK, MET, BRAF, RET, ERBB2, and ROS1) and two established driver genes for malignancies other than LC (PIK3CA and MAP2K1). Study participants were grouped as either smokers (current and former, n = 473) or never-smokers (n = 200) according to self-report tobacco use at enrollment. Our findings indicate a higher overall GA frequency for never-smokers compared to smokers (58 vs. 45.7, p-value < 0.01) with the genes EGFR, KRAS, and PIK3CA displaying the highest prevalence while ERBB2, RET, and ROS1 the lowest. Never-smokers present higher frequencies in seven out of the 10 genes; however, smokers harbor a more complex genomic profile. The clearest differences between groups are seen for EGFR (15.6 vs. 21.5, p-value: < 0.01), PIK3CA (6.8 vs 9.5) and ALK (3.2 vs 7.5) in favor of never-smokers, and KRAS (16.3 vs. 11.5) and MAP2K1 (6.6 vs. 3.5) in favor of smokers. Alterations in these genes are comprised almost exclusively by somatic mutations in EGFR and mainly by fusions in ALK, and only by mutations in PIK3CA, KRAS and MAP2K1. We found clear differences in the genomic landscape by smoking status in LUAD patients from Chile, with potential implications for clinical management in these limited-resource settings.

No abstract available