Project description:Tobacco smoking is responsible for over 90% of lung cancer cases, and yet the precise molecular alterations induced by smoking in lung that develop into cancer and impact survival have remained obscure. We performed gene expression analysis using HG-U133A Affymetrix chips on 135 fresh frozen tissue samples of adenocarcinoma and paired noninvolved lung tissue from current, former and never smokers, with biochemically validated smoking information. ANOVA analysis adjusted for potential confounders, multiple testing procedure, Gene Set Enrichment Analysis, and GO-functional classification were conducted for gene selection. Results were confirmed in independent adenocarcinoma and non-tumor tissues from two studies. We identified a gene expression signature characteristic of smoking that includes cell cycle genes, particularly those involved in the mitotic spindle formation (e.g., NEK2, TTK, PRC1). Expression of these genes strongly differentiated both smokers from non-smokers in lung tumors and early stage tumor tissue from non-tumor tissue (p<0.001 and fold-change>1.5, for each comparison), consistent with an important role for this pathway in lung carcinogenesis induced by smoking. These changes persisted many years after smoking cessation. NEK2 (p<0.001) and TTK (p=0.002) expression in the noninvolved lung tissue was also associated with a 3-fold increased risk of mortality from lung adenocarcinoma in smokers. Our work provides insight into the smoking-related mechanisms of lung neoplasia, and shows that the very mitotic genes known to be involved in cancer development are induced by smoking and affect survival. These genes are candidate targets for chemoprevention and treatment of lung cancer in smokers. Experiment Overall Design: Overall, 180 adenocarcinoma and non-tumor tissue samples were selected for the analyses, including duplicate or triplicate samples from 14 subjects for quality control. From the original 180 samples, 148 provided sufficient quantity of high-quality RNA for microarray analyses; 13 additional samples were excluded because of problematic assays. Normalization was conducted on the remaining 135 microarrays. After normalization, 13 samples were excluded because of low percentage of tumor cells in the tumor tissues. This report is based on 122 samples, of which 15 duplicates were averaged, resulting in 107 final expression values from 58 tumor and 49 non-tumor tissues from 20 never smokers, 26 former smokers, and 28 current smokers.

Project description:ImportanceEstimating absolute risk of lung cancer for never-smoking individuals is important to inform lung cancer screening programs.ObjectivesTo integrate data on environmental tobacco smoke (ETS), a known lung cancer risk factor, with a polygenic risk score (PRS) that captures overall genetic susceptibility, to estimate the absolute risk of lung adenocarcinoma (LUAD) among never-smokers in Taiwan.Design, setting, and participantsThe analyses were conducted in never-smoking women in the Taiwan Genetic Epidemiology Study of Lung Adenocarcinoma, a case-control study. Participants were recruited between September 17, 2002, and March 30, 2011. Data analysis was performed from January 17 to July 15, 2022.ExposuresA PRS was derived using 25 genetic variants that achieved genome-wide significance (P < 5 × 10-8) in a recent genome-wide association study, and ETS was defined as never exposed, exposed at home or at work, and exposed at home and at work.Main outcomes and measuresThe Individualized Coherent Absolute Risk Estimator software was used to estimate the lifetime absolute risk of LUAD in never-smoking women aged 40 years over a projected 40-year span among the controls by using the relative risk estimates for the PRS and ETS exposures, as well as age-specific lung cancer incidence rates for never-smokers in Taiwan. Likelihood ratio tests were conducted to assess an additive interaction between the PRS and ETS exposure.ResultsData were obtained on 1024 women with LUAD (mean [SD] age, 59.6 [11.4] years, 47.9% ever exposed to ETS at home, and 19.5% ever exposed to ETS at work) and 1024 controls (mean [SD] age, 58.9 [11.0] years, 37.0% ever exposed to ETS at home, and 14.3% ever exposed to ETS at work). The overall average lifetime 40-year absolute risk of LUAD estimated using PRS alone was 2.5% (range, 0.6%-10.3%) among women never exposed to ETS. When integrating both ETS and PRS data, the estimated absolute risk was 3.7% (range, 0.6%-14.5%) for women exposed to ETS at home or work and 5.3% (range, 1.2%-12.1%) for women exposed to ETS at home and work. A super-additive interaction between ETS and the PRS (P = 6.5 × 10-4 for interaction) was identified.Conclusions and relevanceThis study found differences in absolute risk of LUAD attributed to genetic susceptibility according to levels of ETS exposure in never-smoking women. Future studies are warranted to integrate these findings in expanded risk models for LUAD.

Project description:ImportanceChinese women have the highest rate of lung cancer among female never-smokers in the world, and the etiology is poorly understood.ObjectiveTo assess the association between metabolomics and lung cancer risk among never-smoking women.Design, setting, and participantsThis nested case-control study included 275 never-smoking female patients with lung cancer and 289 never-smoking cancer-free control participants from the prospective Shanghai Women's Health Study recruited from December 28, 1996, to May 23, 2000. Validated food frequency questionnaires were used for the collection of dietary information. Metabolomic analysis was conducted from November 13, 2015, to January 6, 2016. Data analysis was conducted from January 6, 2016, to November 29, 2018.ExposuresUntargeted ultra-high-performance liquid chromatography-tandem mass spectrometry and nuclear magnetic resonance metabolomic profiles were characterized using prediagnosis urine samples. A total of 39 416 metabolites were measured.Main outcomes and measuresIncident lung cancer.ResultsAmong the 564 women, those who developed lung cancer (275 participants; median [interquartile range] age, 61.0 [52-65] years) and those who did not develop lung cancer (289 participants; median [interquartile range] age, 62.0 [53-66] years) at follow-up (median [interquartile range] follow-up, 10.9 [9.0-11.7] years) were similar in terms of their secondhand smoke exposure, history of respiratory diseases, and body mass index. A peak metabolite, identified as 5-methyl-2-furoic acid, was significantly associated with lower lung cancer risk (odds ratio, 0.57 [95% CI, 0.46-0.72]; P < .001; false discovery rate = 0.039). Furthermore, this peak was weakly correlated with self-reported dietary soy intake (ρ = 0.21; P < .001). Increasing tertiles of this metabolite were associated with lower lung cancer risk (in comparison with first tertile, odds ratio for second tertile, 0.52 [95% CI, 0.34-0.80]; and odds ratio for third tertile, 0.46 [95% CI, 0.30-0.70]), and the association was consistent across different histological subtypes and follow-up times. Additionally, metabolic pathway analysis found several systemic biological alterations that were associated with lung cancer risk, including 1-carbon metabolism, nucleotide metabolism, oxidative stress, and inflammation.Conclusions and relevanceThis prospective study of the untargeted urinary metabolome and lung cancer among never-smoking women in China provides support for the hypothesis that soy-based metabolites are associated with lower lung cancer risk in never-smoking women and suggests that biological processes linked to air pollution may be associated with higher lung cancer risk in this population.

Project description:BackgroundSince several lines of evidence suggest that estrogens may be involved in lung carcinogenesis, it has been hypothesized that intake of phytoestrogens, similar in molecular structure to mammalian estrogens, may be associated with lung cancer development.ObjectiveThe aim was to prospectively evaluate the association between phytoestrogen exposure and lung cancer risk in never-smoking women.MethodsWe conducted a nested case-control study within a population-based prospective cohort study of women. A total of 478 incident lung cancer cases and their individually matched controls were identified among never-smoking women after a mean follow-up of 15.6 years. Habitual intake of and internal exposure to phytoestrogens were assessed by repeated dietary surveys and urinary biomarkers, respectively. ORs and 95% CIs for lung cancer were estimated in conditional logistic regression models.ResultsAfter adjustment for potential confounders, a moderate intake of dietary isoflavones was inversely associated with lung cancer risk in never-smoking women, with the OR for the second quartile vs. the lowest quartile of intake being 0.52 (95% CI: 0.35, 0.76). Further increasing intake did not convey additional benefits, with ORs (95% CI) for the third and fourth quartiles of 0.53 (0.36, 0.78) and 0.47 (0.31, 0.72), respectively (P-overall < 0.001 and P-nonlinearity = 0.006). A similar association was seen when exposure to isoflavones was assessed by urinary biomarkers. ORs (95% CI) for the second, third, and fourth quartiles compared with the lowest quartile of urinary isoflavone excretion were 0.57 (0.39, 0.83), 0.64 (0.44, 0.92), and 0.60 (0.41, 0.86), respectively. The inverse association reached a plateau beyond the second quartile, with P-overall = 0.04 and P-nonlinearity = 0.15. Urinary excretion of gut-microbiota-derived metabolites of lignans was not related to lung cancer risk.ConclusionsThis study suggests that moderately increasing intake of isoflavone-rich foods is associated with lower risk of lung cancer in never-smoking women.

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Evaluating risk factors for lung cancer among never-smoking individuals using two Australian studies.

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Evaluating risk factors for lung cancer among never-smoking individuals using two Australian studies.

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