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Background: Although sex hormones are thought to play an important role in the carcinogenesis of non-small cell lung cancer (NSCLC) in never-smokers, the causative mechanism remains unknown. Passive smoking (PS) is common among East Asian women and has been suggested to be a potential cause of the disease., Methods: We systematically evaluated the expression of estrogen receptor (ER), the prevalence of PS, and genetic mutations using tumor samples from a prospectively registered cohort of never-smokers with lung cancer. The study enrolled 92 never-smokers with NSCLC. Expression of ERa, ERP, and progesterone receptor (PR) was examined via immunohistochemical staining (IHC). Detailed PS information was obtained through a standardized questionnaire. The cumulative dose of PS (CPS) was evaluated as a sum of the number of exposure years at home and/or in the work place., Results: Nuclear expression of ERa, ERP, and PR was detected in 0, 14, and 3 cases, respectively. ERP was more frequently overexpressed in earlier stage cancer (p=0.043). Ninety patients (97.9%) had a PS history, and the median CPS was 47.5 years (range, 0-103 years). There was no significant correlation between the amount of PS -and ERP expression (p=0.101). Twelve patients (85.7%) had Epidermal growth factor receptor ,EGFR) mutations in 14 .tumors expressing ERP, and a trend towards an association between ERP expression and EGFR mutations (p =0.067) was -observed., Conclusions: Nuclear expression of ERP was more frequently observed in early stage NSCLC in never-smokers.

Purpose: Oncogenic driver mutations are critical for lung cancer development and serve as therapeutic targets. However, their associations with environmental factors are not fully understood. We aimed to elucidate the relationship between tumor developmental biology and exposure to environmental factors., Patients and Methods: This was a prospective, multicenter, molecular epidemiology study. Eligible patients were those with newly diagnosed stages I to IIIB non-small-cell lung cancer (NSCLC) who underwent surgery. The tumors were examined for somatic mutations in 72 cancer-associated genes by targeted deep sequencing, estrogen receptor β (ERβ) expression using immunohistochemical staining, and infection with any of 37 types of human papillomavirus (HPV) using a polymerase chain reaction-based microarray system. Detailed information on patient demographics and environmental factors was obtained from a comprehensive questionnaire., Results: From July 2012 to December 2013, 957 patients were enrolled, and molecular analyses were performed on 876 samples (from 441 ever- and 435 never-smokers). Oncogenic driver mutations in P53 and KRAS increased proportionally with smoking status, whereas mutations in EGFR and SMAD4 decreased. KRAS mutations in smokers and SMAD4 mutations were observed more frequently in proportion to body mass index. TP53 and NFE2L2 mutations were observed more frequently in advanced NSCLC stages. As for never-smokers, no environmental factors were significantly associated with mutational changes. EGFR mutations and TP53 mutations were observed more frequently in women and in men, respectively. Mutations in these two genes were also potentially associated with ERβ expression. Only three patients (0.3%) were HPV positive., Conclusion: The mutational spectrum is associated with smoking, body mass index, and other environmental factors, as well as with ERβ expression. Little association was observed between HPV and NSCLC., (© 2016 by American Society of Clinical Oncology.)