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Comprehensive functional annotation of susceptibility variants identifies genetic heterogeneity between lung adenocarcinoma and squamous cell carcinoma.

Authors :
Qin N
Li Y
Wang C
Zhu M
Dai J
Hong T
Albanes D
Lam S
Tardon A
Chen C
Goodman G
Bojesen SE
Landi MT
Johansson M
Risch A
Wichmann HE
Bickeboller H
Rennert G
Arnold S
Brennan P
Field JK
Shete S
Le Marchand L
Melander O
Brunnstrom H
Liu G
Hung RJ
Andrew A
Kiemeney LA
Zienolddiny S
Grankvist K
Johansson M
Caporaso N
Woll P
Lazarus P
Schabath MB
Aldrich MC
Stevens VL
Jin G
Christiani DC
Hu Z
Amos CI
Ma H
Shen H
Source :
Frontiers of medicine [Front Med] 2021 Apr; Vol. 15 (2), pp. 275-291. Date of Electronic Publication: 2020 Sep 05.
Publication Year :
2021

Abstract

Although genome-wide association studies have identified more than eighty genetic variants associated with non-small cell lung cancer (NSCLC) risk, biological mechanisms of these variants remain largely unknown. By integrating a large-scale genotype data of 15 581 lung adenocarcinoma (AD) cases, 8350 squamous cell carcinoma (SqCC) cases, and 27 355 controls, as well as multiple transcriptome and epigenomic databases, we conducted histology-specific meta-analyses and functional annotations of both reported and novel susceptibility variants. We identified 3064 credible risk variants for NSCLC, which were overrepresented in enhancer-like and promoter-like histone modification peaks as well as DNase I hypersensitive sites. Transcription factor enrichment analysis revealed that USF1 was AD-specific while CREB1 was SqCC-specific. Functional annotation and gene-based analysis implicated 894 target genes, including 274 specifics for AD and 123 for SqCC, which were overrepresented in somatic driver genes (ER = 1.95, P = 0.005). Pathway enrichment analysis and Gene-Set Enrichment Analysis revealed that AD genes were primarily involved in immune-related pathways, while SqCC genes were homologous recombination deficiency related. Our results illustrate the molecular basis of both well-studied and new susceptibility loci of NSCLC, providing not only novel insights into the genetic heterogeneity between AD and SqCC but also a set of plausible gene targets for post-GWAS functional experiments.

Details

Language :
English
ISSN :
2095-0225
Volume :
15
Issue :
2
Database :
MEDLINE
Journal :
Frontiers of medicine
Publication Type :
Academic Journal
Accession number :
32889700
Full Text :
https://doi.org/10.1007/s11684-020-0779-4