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Association Analysis of Driver Gene-Related Genetic Variants Identified Novel Lung Cancer Susceptibility Loci with 20,871 Lung Cancer Cases and 15,971 Controls

Wang, Yuzhuo ; Gorlova, Olga Y. ; Gorlov, Ivan P. ; Zhu, Meng ; Dai, Juncheng ; Albanes, Demetrius ; Lam, Stephen ; Tardon, Adonina ; Chen, Chu and Goodman, Gary E. , et al. (2020) In Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology 29(7). p.1423-1429
Abstract

BACKGROUND: A substantial proportion of cancer driver genes (CDG) are also cancer predisposition genes. However, the associations between genetic variants in lung CDGs and the susceptibility to lung cancer have rarely been investigated. METHODS: We selected expression-related single-nucleotide polymorphisms (eSNP) and nonsynonymous variants of lung CDGs, and tested their associations with lung cancer risk in two large-scale genome-wide association studies (20,871 cases and 15,971 controls of European descent). Conditional and joint association analysis was performed to identify independent risk variants. The associations of independent risk variants with somatic alterations in lung CDGs or recurrently altered pathways were investigated... (More)

BACKGROUND: A substantial proportion of cancer driver genes (CDG) are also cancer predisposition genes. However, the associations between genetic variants in lung CDGs and the susceptibility to lung cancer have rarely been investigated. METHODS: We selected expression-related single-nucleotide polymorphisms (eSNP) and nonsynonymous variants of lung CDGs, and tested their associations with lung cancer risk in two large-scale genome-wide association studies (20,871 cases and 15,971 controls of European descent). Conditional and joint association analysis was performed to identify independent risk variants. The associations of independent risk variants with somatic alterations in lung CDGs or recurrently altered pathways were investigated using data from The Cancer Genome Atlas (TCGA) project. RESULTS: We identified seven independent SNPs in five lung CDGs that were consistently associated with lung cancer risk in discovery (P < 0.001) and validation (P < 0.05) stages. Among these loci, rs78062588 in TPM3 (1q21.3) was a new lung cancer susceptibility locus (OR = 0.86, P = 1.65 × 10-6). Subgroup analysis by histologic types further identified nine lung CDGs. Analysis of somatic alterations found that in lung adenocarcinomas, rs78062588[C] allele (TPM3 in 1q21.3) was associated with elevated somatic copy number of TPM3 (OR = 1.16, P = 0.02). In lung adenocarcinomas, rs1611182 (HLA-A in 6p22.1) was associated with truncation mutations of the transcriptional misregulation in cancer pathway (OR = 0.66, P = 1.76 × 10-3). CONCLUSIONS: Genetic variants can regulate functions of lung CDGs and influence lung cancer susceptibility. IMPACT: Our findings might help unravel biological mechanisms underlying lung cancer susceptibility.

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organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology
volume
29
issue
7
pages
7 pages
publisher
American Association for Cancer Research
external identifiers
  • pmid:32277007
  • scopus:85087469658
ISSN
1538-7755
DOI
10.1158/1055-9965.EPI-19-1085
language
English
LU publication?
yes
id
5c0ebc42-b6d3-499c-9949-522efb35506f
date added to LUP
2020-07-16 09:01:29
date last changed
2020-08-10 07:45:33
@article{5c0ebc42-b6d3-499c-9949-522efb35506f,
  abstract     = {<p>BACKGROUND: A substantial proportion of cancer driver genes (CDG) are also cancer predisposition genes. However, the associations between genetic variants in lung CDGs and the susceptibility to lung cancer have rarely been investigated. METHODS: We selected expression-related single-nucleotide polymorphisms (eSNP) and nonsynonymous variants of lung CDGs, and tested their associations with lung cancer risk in two large-scale genome-wide association studies (20,871 cases and 15,971 controls of European descent). Conditional and joint association analysis was performed to identify independent risk variants. The associations of independent risk variants with somatic alterations in lung CDGs or recurrently altered pathways were investigated using data from The Cancer Genome Atlas (TCGA) project. RESULTS: We identified seven independent SNPs in five lung CDGs that were consistently associated with lung cancer risk in discovery (P &lt; 0.001) and validation (P &lt; 0.05) stages. Among these loci, rs78062588 in TPM3 (1q21.3) was a new lung cancer susceptibility locus (OR = 0.86, P = 1.65 × 10-6). Subgroup analysis by histologic types further identified nine lung CDGs. Analysis of somatic alterations found that in lung adenocarcinomas, rs78062588[C] allele (TPM3 in 1q21.3) was associated with elevated somatic copy number of TPM3 (OR = 1.16, P = 0.02). In lung adenocarcinomas, rs1611182 (HLA-A in 6p22.1) was associated with truncation mutations of the transcriptional misregulation in cancer pathway (OR = 0.66, P = 1.76 × 10-3). CONCLUSIONS: Genetic variants can regulate functions of lung CDGs and influence lung cancer susceptibility. IMPACT: Our findings might help unravel biological mechanisms underlying lung cancer susceptibility.</p>},
  author       = {Wang, Yuzhuo and Gorlova, Olga Y. and Gorlov, Ivan P. and Zhu, Meng and Dai, Juncheng and Albanes, Demetrius and Lam, Stephen and Tardon, Adonina and Chen, Chu and Goodman, Gary E. and Bojesen, Stig E. and Landi, Maria Teresa and Johansson, Mattias and Risch, Angela and Wichmann, Heunz Erich and Bickeboller, Heike and Christiani, David C. and Rennert, Gad and Arnold, Susanne M. and Brennan, Paul and Field, John K. and Shete, Sanjay and Le Marchand, Loïc and Melander, Olle and Brunnstrom, Hans and Liu, Geoffrey and Hung, Rayjean J. and Andrew, Angeline S. and Kiemeney, Lambertus A. and Zienolddiny, Shanbeh and Grankvist, Kjell and Johansson, Mikael and Caporaso, Neil E. and Woll, Penella J. and Lazarus, Philip and Schabath, Matthew B. and Aldrich, Melinda C. and Stevens, Victoria L. and Ma, Hongxia and Jin, Guangfu and Hu, Zhibin and Amos, Christopher I. and Shen, Hongbing},
  issn         = {1538-7755},
  language     = {eng},
  number       = {7},
  pages        = {1423--1429},
  publisher    = {American Association for Cancer Research},
  series       = {Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology},
  title        = {Association Analysis of Driver Gene-Related Genetic Variants Identified Novel Lung Cancer Susceptibility Loci with 20,871 Lung Cancer Cases and 15,971 Controls},
  url          = {http://dx.doi.org/10.1158/1055-9965.EPI-19-1085},
  doi          = {10.1158/1055-9965.EPI-19-1085},
  volume       = {29},
  year         = {2020},
}