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Olle Melander

Principal investigator

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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

Author

  • 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 Brennan
  • John K. Field
  • Sanjay Shete
  • Loïc 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

Summary, in English

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.

Department/s

  • Cardiovascular Research - Hypertension
  • EpiHealth: Epidemiology for Health
  • EXODIAB: Excellence in Diabetes Research in Sweden
  • LUCC - Lund University Cancer Centre
  • Improved diagnostics and prognostics of lung cancer and metastases to the lungs

Publishing year

2020

Language

English

Pages

1423-1429

Publication/Series

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

Document type

Journal article

Publisher

American Association for Cancer Research

Topic

  • Cancer and Oncology
  • Medical Genetics

Status

Published

Research group

  • Cardiovascular Research - Hypertension
  • Improved diagnostics and prognostics of lung cancer and metastases to the lungs

ISBN/ISSN/Other

  • ISSN: 1538-7755