br Acknowledgments Dr Calin is The Alan M Gewirtz

Acknowledgments Dr Calin is The Alan M. Gewirtz Leukemia & Lymphoma Society Scholar. Work in Dr. Calin\'s laboratory is supported in part by the NIH/NCI grants 1UH2TR00943-01 and 1 R01 CA182905-01, the UT MD Anderson Cancer Center SPORE in Melanoma grant from NCI (P50 CA093459), Aim at Melanoma Foundation and the Miriam and Jim Mulva research funds, the Brain SPORE (2P50CA127001), the Center for Radiation Oncology Research Project, the Center for Cancer Epigenetics Pilot project, a 2014 Knowledge GAP MDACC grant, a CLL Moonshot pilot project, the UT MD Anderson Cancer Center Duncan Family Institute for Cancer Prevention and Risk Assessment, a SINF grant in colon cancer, the Laura and John Arnold Foundation, the RGK Foundation and the Estate of C. G. Johnson, Jr. This research was partially supported by the P01-CA81534 and the CLL Research Consortium to Drs. Rassenti and Kipps. Dr. Kay is the recipient of NCI research award CA95241 and support from the CLL Research Consortium and the CLL Global Foundation. Dr. Shanafelt is a Clinical Scholar of the Leukemia and Lymphoma Society. Dr Van Roosbroeck was a Henri Benedictus Fellow of the King Baudouin Foundation and the Belgian American Education Foundation (B.A.E.F.). Dr Ciccone was supported by AIL-Associazione Italiana contro le Leucemie Sezione di Ferrara.
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Introduction Air pollution is a significant environmental risk factor for lung cancer. For every increase of 5μg/m3 of particulate order GSK2126458 (PM) smaller than 2.5μm in diameter (PM2.5) in the environment, the risk of lung cancer rises by 18%; for every elevation of 10μg/m3 in PM smaller than 10μm (PM10), the risk increases by 22% (Raaschou-Nielsen et al., 2013). Anthropogenic PM2.5 is associated with 220,000 lung cancer mortalities annually (Anenberg et al., 2010). Based on sufficient evidence of carcinogenicity, the International Agency for Research on Cancer (IARC) Working Group recently classified outdoor air pollution and related PM as Group 1 carcinogenic to humans (Loomis et al., 2013). However, the carcinogenic mechanism of air pollution remains to be dissected using systematic approaches. Xuanwei (XW) City in Yunnan Province of China (Fig. S1), provides an example of the epidemiological association between PM10, PM2.5 and lung cancer (Xiao et al., 2012; Cao and Gao, 2012; Mumford et al., 1987). This city and the neighboring Fuyuan (FY) county have a large deposit of smoky coal (Mumford et al., 1987). Until the 1970s, residents of these regions used smoky coal in unvented indoor fire pits for domestic cooking and heating, all processes that release high concentrations of PM10 and PM2.5. These airborne particles contain high concentrations of polycyclic aromatic hydrocarbons (PAHs) including benzo(a)pyrene (BaP) and polar compounds that are highly mutagenic (Mumford et al., 1987). Lung cancer incidence in XW is among the highest in China (Mumford et al., 1987; Xiao et al., 2012), and a reduction in lung cancer morbidity was noted in the 1990s after stove improvement in central XW, supporting the association between air pollution and lung cancer (Lan et al., 2002). The findings in XW had been cited in the IARC monograph classifying indoor emissions from household combustion of coal as “carcinogenic to humans (Group 1)” (World Health Organization International Agency for Research on Cancer, 2010). However, the overall lung cancer incidence in this region has been increasing (Xiao et al., 2012; Chen, 2008), possibly due to pollutants generated by coal-burning industrial plants that moved into the area (Cao and Gao, 2012). In 2011, a survey (Li et al., 2011) of 52,833 residents living in 382 rural villages in XW/FY reported 363 subjects diagnosed with lung cancer, with the world age-standardized rate (ASR) of 426/100,000 in some regions of XW. Population in these highly polluted regions (HPR) lends a unique opportunity to dissect the carcinogenesis that is specifically related to air pollution, and we took this opportunity by sequencing the whole genomes of lung cancers from these regions to provide a comprehensive landscape of genomic alterations in this study.