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The genomic landscape of nonsmall cell lung carcinoma in never smokers
Author(s) -
Boeckx Bram,
Shahi Rajendra B.,
Smeets Dominiek,
De Brakeleer Sylvia,
Decoster Lore,
Van Brussel Thomas,
Galdermans Daniella,
Vercauter Piet,
Decoster Lynn,
Alexander Patrick,
Berchem Guy,
Ocak Sebahat,
Vuylsteke Peter,
Deschepper Koen,
Lambrechts Marc,
Cappoen Nadia,
Teugels Erik,
Lambrechts Diether,
De Greve Jacques
Publication year - 2019
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.32797
Subject(s) - lung cancer , oncology , medicine , germline mutation , cancer , carcinoma , somatic cell , adenocarcinoma , exome sequencing , mutation , cancer research , bioinformatics , genetics , biology , gene
Lung cancer is the number one cause of cancer‐related death worldwide with cigarette smoking as its major risk factor. Although the incidence of lung cancer in never smokers is rising, this subgroup of patients is underrepresented in genomic studies of lung cancer. Here, we assembled a prospective cohort of 46 never‐smoking, nonsmall cell lung cancer (NSCLC) patients and performed whole‐exome and low‐coverage whole‐genome sequencing on tumors and matched germline DNA. We observed fewer somatic mutations, genomic breakpoints and a smaller fraction of the genome with chromosomal instability in lung tumors from never smokers compared to smokers. The lower number of mutations, enabled us to identify TSC22D1 as a potential driver gene in NSCLC. On the other hand, the frequency of mutations in actionable genes such as EGFR and ERBB2 and of amplifications in MET were higher, while the mutation rate of TP53 , which is a negative prognostic factor, was lower in never smokers compared to smokers. Together, these observations suggest a more favorable prognosis for never smokers with NSCLC. Classification of somatic mutations into six‐substitution type patterns or into 96‐substitution type signatures revealed distinct clusters between smokers and never smokers. Particularly, we identified in never smokers signatures related to aging, homologous recombination damage and APOBEC/AID activity as the most important underlying processes of NSCLC. This further indicates that second‐hand smoking is not driving NSCLC pathogenesis in never smokers.