EGAGenomicsN/Ahttps://ega-archive.org/datasets/EGAD0000100528768EGA dataset EGAD00001005287EGAOur understanding of genomic heterogeneity in lung cancer is largely based on the analysis of early-stage surgical specimens. Here we used endoscopic sampling of paired primary and intrathoracic metastatic tumors from 11 lung cancer patients to map genomic heterogeneity inoperable lung cancer with deep whole-genome sequencing. Intra-patient heterogeneity in driver or targetable mutations was predominantly in the form of copy number gain. Private mutation signatures, including patterns consistent with defects in homologous recombination, were highly variable both within and between patients. Irrespective of histotype, we observed a smaller than expected number of private mutations, suggesting that ancestral clones accumulated large mutation burdens immediately prior to metastasis. Single-region whole-genome sequencing of from 20 patients showed that tumors in ever-smokers with the strongest tobacco signatures were associated with germline variants in genes implicated in the repair of cigarette-induced DNA damage. Our results suggest that lung cancer precursors in ever-smokers accumulate large numbers of mutations prior to the formation of frank malignancy followed by rapid metastatic spread. In advanced lung cancer, germline variants in DNA repair genes may interact with the airway environment to influence the pattern of founder mutations, whereas similar interactions with the tumor microenvironment may play a role in the acquisition of mutations following metastasis.Deep multi-region whole-genome sequencing reveals heterogeneity and gene-by-environment interactions in treatment-naive, metastatic lung cancer.Leong Tracy L TL, Gayevskiy Velimir V, Steinfort Daniel P DP, De Massy Marc R MR, Gonzalez-Rajal Alvaro A, Marini Kieren D KD, Stone Emily E, Chin Venessa V, Havryk Adrian A, Plit Marshall M, Irving Louis B LB, Jennings Barton R BR, McCloy Rachael A RA, Jayasekara W Samantha N WSN, Alamgeer Muhammad M, Boolell Vishal V, Field Andrew A, Russell Prudence A PA, Kumar Beena B, Gough Daniel J DJ, Gough Daniel J DJ, Szczepny Anette A, Ganju Vinod V, Rossello Fernando J FJ, Cain Jason E JE, Papenfuss Anthony T AT, Asselin-Labat Marie-Liesse ML, Cowley Mark J MJ, Watkins D Neil DNfalse5b85420b-44cf-4d0a-9fa8-4930e698bc25 - samplesDeep WGS (germline and 2-5 tumour regions) was performed on 20 patients: 13 lung adenocarcinoma, 5 squamous cell carcinoma, 2 small-cell lung cancers. A total of 68 BAM files are provided, where tumours were sequenced to 60x or 150x depth.2019-12-10 13:51:37EGAD00001005287960630348992EGAC00001001300EGAS00001003830