The genomic landscape of nonsmall cell lung carcinoma in never smokers.
Carcinoma, Non-Small-Cell Lung
/ genetics
ErbB Receptors
/ genetics
Humans
Lung
/ pathology
Lung Neoplasms
/ genetics
Mutation
/ genetics
Non-Smokers
Prospective Studies
Receptor, ErbB-2
/ genetics
Repressor Proteins
/ genetics
Risk Factors
Smoking
/ adverse effects
Tobacco Smoke Pollution
/ adverse effects
Tumor Suppressor Protein p53
/ genetics
Exome Sequencing
Whole Genome Sequencing
lung cancer
never smokers
whole-exome sequencing
Journal
International journal of cancer
ISSN: 1097-0215
Titre abrégé: Int J Cancer
Pays: United States
ID NLM: 0042124
Informations de publication
Date de publication:
01 06 2020
01 06 2020
Historique:
received:
28
03
2019
revised:
11
10
2019
accepted:
15
10
2019
pubmed:
21
11
2019
medline:
8
1
2021
entrez:
21
11
2019
Statut:
ppublish
Résumé
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.
Substances chimiques
Repressor Proteins
0
TP53 protein, human
0
TSC22D1 protein, human
0
Tobacco Smoke Pollution
0
Tumor Suppressor Protein p53
0
EGFR protein, human
EC 2.7.10.1
ERBB2 protein, human
EC 2.7.10.1
ErbB Receptors
EC 2.7.10.1
Receptor, ErbB-2
EC 2.7.10.1
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
3207-3218Informations de copyright
© 2019 UICC.
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