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

Qin, Na ; Li, Yuancheng ; Wang, Cheng ; Zhu, Meng ; Dai, Juncheng ; Hong, Tongtong ; Albanes, Demetrius ; Lam, Stephen ; Tardon, Adonina and Chen, Chu , et al. (2021) In Frontiers of Medicine 15(2). p.275-291
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... (More)

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.

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organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
function annotation, genetic heterogeneity, genome-wide association study, homologous recombination repair deficiency, immune, lung cancer
in
Frontiers of Medicine
volume
15
issue
2
pages
17 pages
publisher
Springer
external identifiers
  • scopus:85090192677
  • pmid:32889700
ISSN
2095-0217
DOI
10.1007/s11684-020-0779-4
language
English
LU publication?
yes
id
c7d705a1-e2d8-4451-b44c-038d6c0ddb5b
date added to LUP
2020-09-28 09:58:48
date last changed
2025-01-10 18:42:34
@article{c7d705a1-e2d8-4451-b44c-038d6c0ddb5b,
  abstract     = {{<p>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.</p>}},
  author       = {{Qin, Na and Li, Yuancheng and Wang, Cheng and Zhu, Meng and Dai, Juncheng and Hong, Tongtong and Albanes, Demetrius and Lam, Stephen and Tardon, Adonina and Chen, Chu and Goodman, Gary and Bojesen, Stig E. and Landi, Maria Teresa and Johansson, Mattias and Risch, Angela and Wichmann, H. Erich and Bickeboller, Heike and Rennert, Gadi and Arnold, Susanne and Brennan, Paul and Field, John K. and Shete, Sanjay and Le Marchand, Loic and Melander, Olle and Brunnstrom, Hans and Liu, Geoffrey and Hung, Rayjean J. and Andrew, Angeline and Kiemeney, Lambertus A. and Zienolddiny, Shan and Grankvist, Kjell and Johansson, Mikael and Caporaso, Neil and Woll, Penella and Lazarus, Philip and Schabath, Matthew B. and Aldrich, Melinda C. and Stevens, Victoria L. and Jin, Guangfu and Christiani, David C. and Hu, Zhibin and Amos, Christopher I. and Ma, Hongxia and Shen, Hongbing}},
  issn         = {{2095-0217}},
  keywords     = {{function annotation; genetic heterogeneity; genome-wide association study; homologous recombination repair deficiency; immune; lung cancer}},
  language     = {{eng}},
  month        = {{04}},
  number       = {{2}},
  pages        = {{275--291}},
  publisher    = {{Springer}},
  series       = {{Frontiers of Medicine}},
  title        = {{Comprehensive functional annotation of susceptibility variants identifies genetic heterogeneity between lung adenocarcinoma and squamous cell carcinoma}},
  url          = {{http://dx.doi.org/10.1007/s11684-020-0779-4}},
  doi          = {{10.1007/s11684-020-0779-4}},
  volume       = {{15}},
  year         = {{2021}},
}