TY - JOUR
T1 - The genomic landscape of nonsmall cell lung carcinoma in never smokers
AU - Boeckx, Bram
AU - Shahi, Rajendra B.
AU - Smeets, Dominiek
AU - De Brakeleer, Sylvia
AU - Decoster, Lore
AU - Van Brussel, Thomas
AU - Galdermans, Daniella
AU - Vercauter, Piet
AU - Decoster, Lynn
AU - Alexander, Patrick
AU - Berchem, Guy
AU - Ocak, Sebahat
AU - Vuylsteke, Peter
AU - Deschepper, Koen
AU - Lambrechts, Marc
AU - Cappoen, Nadia
AU - Teugels, Erik
AU - Lambrechts, Diether
AU - De Greve, Jacques
N1 - Funding Information:
Our study was supported by the National Cancer Plan Project 29‐03 (JDG and DL). The computational resources and services used in this work were provided by the Flemish Supercomputer Center (VSC), funded by the Hercules Foundation, Department of Economy, Science and Innovation from the Flemish government (EWI). Scientific Fund W Gepts (JDG and LDC) of the UZ Brussel.
Funding Information:
Our study was supported by the National Cancer Plan Project 29-03 (JDG and DL). The computational resources and services used in this work were provided by the Flemish Supercomputer Center (VSC), funded by the Hercules Foundation, Department of Economy, Science and Innovation from the Flemish government (EWI). Scientific Fund W Gepts (JDG and LDC) of the UZ Brussel.
Publisher Copyright:
© 2019 UICC
PY - 2020/6/1
Y1 - 2020/6/1
N2 - 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.
AB - 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.
KW - lung cancer
KW - never smokers
KW - whole-exome sequencing
UR - http://www.scopus.com/inward/record.url?scp=85076554507&partnerID=8YFLogxK
U2 - 10.1002/ijc.32797
DO - 10.1002/ijc.32797
M3 - Article
C2 - 31745979
AN - SCOPUS:85076554507
SN - 0020-7136
VL - 146
SP - 3207
EP - 3218
JO - International Journal of Cancer
JF - International Journal of Cancer
IS - 11
ER -