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BackgroundWe previously found that occupational exposure to diesel engine exhaust (DEE) was associated with alterations to 19 biomarkers that potentially reflect the mechanisms of carcinogenesis. Whether DEE is associated with biological alterations at concentrations under existing or recommended occupational exposure limits (OELs) is unclear.MethodsIn a cross-sectional study of 54 factory workers exposed long-term to DEE and 55 unexposed controls, we reanalysed the 19 previously identified biomarkers. Multivariable linear regression was used to compare biomarker levels between DEE-exposed versus unexposed subjects and to assess elemental carbon (EC) exposure-response relationships, adjusted for age and smoking status. We analysed each biomarker at EC concentrations below the US Mine Safety and Health Administration (MSHA) OEL (3), below the European Union (EU) OEL (3) and below the American Conference of Governmental Industrial Hygienists (ACGIH) recommendation (3).ResultsBelow the MSHA OEL, 17 biomarkers were altered between DEE-exposed workers and unexposed controls. Below the EU OEL, DEE-exposed workers had elevated lymphocytes (p=9E-03, false discovery rate (FDR)=0.04), CD4+ count (p=0.02, FDR=0.05), CD8+ count (p=5E-03, FDR=0.03) and miR-92a-3p (p=0.02, FDR=0.05), and nasal turbinate gene expression (first principal component: p=1E-06, FDR=2E-05), as well as decreased C-reactive protein (p=0.02, FDR=0.05), macrophage inflammatory protein-1β (p=0.04, FDR=0.09), miR-423-3p (p=0.04, FDR=0.09) and miR-122-5p (p=2E-03, FDR=0.02). Even at EC concentrations under the ACGIH recommendation, we found some evidence of exposure-response relationships for miR-423-3p (ptrend=0.01, FDR=0.19) and gene expression (ptrend=0.02, FDR=0.19).ConclusionsDEE exposure under existing or recommended OELs may be associated with biomarkers reflective of cancer-related processes, including inflammatory/immune response.

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: The etiology of lung cancer among never-smokers has not been adequately elucidated despite that globally15% of lung cancer cases in men and 53% in women are not smoking-related. Epigenetic modifications, including changes in DNA methylation (DNAm), have been suggested as possible underlying mechanisms. However, only a few prospective epigenome-wide association studies (EWAS) of lung cancer incidence have been conducted, all exclusively focused on DNAm in peripheral blood cells and included a minimal number of never-smokers. We aimed to investigate genome-wide DNAm associations and epigenetic age acceleration with future risk of lung cancer among never-smokers using pre-diagnostic oral rinse samples. Methods: We conducted a case-control study of 80 never-smoking incident lung cancer cases and 83 comparable never-smoking controls nested in two large prospective cohorts: the Shanghai Women’s Health Study and Shanghai Men’s Health Study. DNAm was measured using the Illumina EPIC array. The top 50 differentially methylated positions (DMPs) were identified from a discovery sample and tested for replication in a validation sample using robust linear regression models. We also conducted an EWAS in the pooled sample. We examined functional overlap enrichment across chromatin states and histone mark broadPeaks for the top 1000 DMPs using eFORGE and constructed enrichment biological pathways analyses. Results: Across discovery and pooled EWAS, we identified four DMPs associated with lung cancer at the epigenome-wide significance level of P Conclusions: To our knowledge, this is the first prospective EWAS of lung cancer among never-smokers using oral rinse samples. Our results show that DNAm in pre-diagnostic oral rinse samples can provide new insights into lung cancer etiology and risk factors. Citation Format: Mohammad L. Rahman, Charles E. Breeze, Xiao-Ou Shu, Jason YY Wong, Andres Cardenas, Xuting Wang, Bu-Tian Ji, Wei Hu, Batel Blechter, Qiuyin Cai, H Dean Hosgood, Gong Yang, Jianxin Shi, Jirong Long, Yu-Tang Gao, Douglas Bell, Wei Zheng, Qing Lan, Nathaniel Rothman. Epigenome-wide association study of lung cancer among never-smokers in two prospective cohorts in Shanghai [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 3483.

Diesel engine exhaust (DEE) is a known lung carcinogen and may be associated with other tumors, however, the mechanisms of action by which DEE causes cancer is not well understood. MicroRNAs (miRNAs), which are small non-coding RNA molecules that play a role in post-transcriptional regulation of gene expression, are altered in multiple tumors and have been observed to be differentially expressed in a variety of biospecimen types in smokers as well as in relation to short-term air pollution exposure. To evaluate whether serum levels of miRNAs are altered in healthy workers occupationally exposed to DEE, we analyzed samples collected in a cross-sectional molecular epidemiology study of diesel engine truck testing facility workers and comparable unexposed controls in China. A panel of 44 miRNAs were measured in 46 workers exposed to relatively high air levels of DEE and 45 controls using the Fireplex circulating miRNA assay (Abcam, Inc.), which profiles miRNAs directly from biofluids. The exposure-response relationship between categorical EC levels and each miRNA was analyzed by linear regression adjusted for age, body mass index, smoking status, current alcohol use and recent infection. We identified two miRNAs that showed a monotonic inverse exposure-response association with DEE: miR-191-5p and miR-93-5p. Levels of miR-191-5p in arbitrary units (A.U.) of fluorescence were 400.7, 333.0, 322.6, and 260.0 in controls and across increasing tertiles of EC, respectively (p for trend = 0.001, FDR = 0.05). Levels of miR-93-5p were 747.1, 713.7, 720.5, and 625.4 A.U. in controls and increasing tertiles of EC, respectively (p for trend = 0.008, FDR = 0.18). Both miRNAs have been reported to influence several biological processes important in carcinogenesis. Our results suggest that occupational exposure to DEE may affect circulating miRNAs in healthy workers. Citation Format: Wei Hu, Bryan A. Bassig, Yufei Dai, Dianzhi Ren, Huawei Duan, Yong Niu, Jun Xu, Wei Fu, Kees Meliefste, Baosen Zhou, Jufang Yang, Meng Ye, Xiaowei Jia, Tao Meng, Ping Bin, Jason YY Wong, Dean H. Hosgood, Nathaniel Rothman, Roel C. Vermeulen, Debra T. Silverman, Yuxin Zheng, Qing Lan. Occupational exposure to diesel engine exhaust and alternations in serum microRNAs [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 597.

The lung cancer rate among never-smokers is the highest among Asian women, however its etiology and any relevant non-smoking related biomarkers are still unclear. Pre-diagnostic lung cancer-related metabolic biomarkers may provide novel insights into lung cancer mechanisms, and may contribute to the discovery of etiologic factors for the high lung cancer prevalence among Asian women. We evaluated the role of the urinary metabolome in lung cancer development among female never-smokers in China by conducting a nested case-control study of 275 lung cancer cases and 289 healthy controls from the Shanghai Women's Health Study, a prospective cohort comprised of 73,363 Chinese female never-smokers. Metabolic profiling of urinary chemical features was conducted using ultrahigh-performance liquid chromatography - tandem mass spectrometry (UPLC-MS) (39,409 spectral features) and 600 MHz 1H nuclear magnetic resonance (NMR) spectroscopy (386 features). Unconditional logistic regression models were used to estimate the odds ratios (ORs) and 95% confidence intervals (CIs) for the association between each log-transformed metabolite level and lung cancer risk, adjusting for potential confounders such as age, body mass index, history of respiratory disease and passive smoking. Spearman correlation and linear regression were used to estimate associations between the most significant metabolites and pre-diagnosis dietary factors. Three detected UPLC-MS urinary metabolites were negatively associated with lung cancer risk with a false discovery rate of less than 10%: pos_2.61_127.0382m/z (OR = 0.57, 95% CI = 0.46-0.72, P = 1.98 x 10-6), neg_2.60_369.0408m/z (OR = 0.97, 95% CI = 0.96-0.98, P = 1.36 x 10-6), and pos_2.61_184.0325n (OR = 0.55, 95% CI = 0.43-0.71, P = 4.91 x 10-6). These were strongly correlated with each other (rho > 0.65, p < 0.0001). The significant metabolite (pos_2.61_127.0382m/z) was identified as 5-methyl-2-furoic acid and was moderately correlated with self-reported dietary intake of soy (rho = 0.21, p < 0.001). In conclusion, we identified a metabolite in urine (5-methyl-2-furoic acid) that provides support for the protective association of soy-based foods on lung cancer risk that was previously observed in this population of never-smoking women. Further studies are warranted to replicate these findings. Citation Format: Wei Jie Seow, Xiao-Ou Shu, Jeremy Nicholson, Elaine Holmes, Wei Hu, Qiuyin Cai, Yu-Tang Gao, Yong-Bing Xiang, Steve Moore, Bryan A. Bassig, Jason Yy Wong, Jinming Zhang, Bu-Tian Ji, Claire Boulange, Manuja Kaluarachchi, Kyrillos F. Adesina-Georgiadis, Anisha Wijeyesekera, Wei Zheng, Paul Elliot, Nathaniel Rothman, Qing Lan. Prospective study of untargeted urinary metabolomics and risk of lung cancer among female never-smokers in Shanghai, China [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4974.