Association analysis of driver gene⇓related genetic variants identified novel lung cancer susceptibility loci with 20,871 lung cancer cases and 15,971 controls

Yuzhuo Wang, Olga Y. Gorlova, Ivan P. Gorlov, Meng Zhu, Juncheng Dai, Demetrius Albanes, Stephen Lam, Adonina Tardon, Chu Chen, Gary E. Goodman, Stig E. Bojesen, Maria Teresa Landi, Mattias Johansson, Angela Risch, Heunz Erich Wichmann, Heike Bickeboller, David C. Christiani, Gad Rennert, Susanne M. Arnold, Paul BrennanJohn K. Field, Sanjay Shete, Loc Le Marchand, Olle Melander, Hans Brunnstrom, Geoffrey Liu, Rayjean J. Hung, Angeline S. Andrew, Lambertus A. Kiemeney, Shanbeh Zienolddiny, Kjell Grankvist, Mikael Johansson, Neil E. Caporaso, Penella J. Woll, Philip Lazarus, Matthew B. Schabath, Melinda C. Aldrich, Victoria L. Stevens, Hongxia Ma, Guangfu Jin, Zhibin Hu, Christopher I. Amos, Hongbing Shen

Research output: Contribution to journalArticlepeer-review

3 Scopus citations

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 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 ¼ 0.86, P ¼ 1.65 106). 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 ¼ 1.16, P ¼ 0.02). In lung adenocarcinomas, rs1611182 (HLA-A in 6p22.1) was associated with truncation mutations of the transcriptional misregulation in cancer pathway (OR ¼ 0.66, P ¼ 1.76 103). 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.

Original languageEnglish
Pages (from-to)1423-1429
Number of pages7
JournalCancer Epidemiology Biomarkers and Prevention
Volume29
Issue number7
DOIs
StatePublished - Jul 2020

Bibliographical note

Funding Information:
The authors thank the study participants and research staff for their contributions and commitment to this study. H. Shen was awarded grants from National Natural Science of China (81820108028, 81521004). C.I. Amos was awarded grants from the NIH (U19 CA148127, U19 CA203654) and the Cancer Prevention Research Institute of Texas (RR170048). H. Ma was awarded a grant from National Natural Science of China (81922061). D.C. Christiani was awarded a grant from the NIH (U01 CA209414). C. Chen was awarded grants from the NIH (U01-CA063673, UM1-CA167462, and U01-CA167462). M.B. Schabath was awarded the Moffitt Cancer Center Support Grant (P30 CA076292) and SPORE in Lung Cancer (P50 CA119997).

Publisher Copyright:
© 2020 American Association for Cancer Research.

ASJC Scopus subject areas

  • Epidemiology
  • Oncology

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