Genome-wide association meta-analysis identifies pleiotropic risk loci for aerodigestive squamous cell cancers

Corina Lesseur, Aida Ferreiro-Iglesias, James D. McKay, Yohan Bossé, Mattias Johansson, Valerie Gaborieau, Maria Teresa Landi, David C. Christiani, Neil C. Caporaso, Stig E. Bojesen, Christopher I. Amos, Sanjay Shete, Geoffrey Liu, Gadi Rennert, Demetrios Albanes, Melinda C. Aldrich, Adonina Tardon, Chu Chen, Liloglou Triantafillos, John K. FieldMarion Dawn Teare, Lambertus A. Kiemeney, Brenda Diergaarde, Robert L. Ferris, Shanbeh Zienolddiny, Stephen Lam, Andrew F. Olshan, Mark C. Weissler, Martin Lacko, Angela Risch, Heike Bickeböller, Andy R. Ness, Steve Thomas, Loic Le Marchand, Matthew B. Schabath, Victor Wünsch-Filho, Eloiza H. Tajara, Angeline S. Andrew, Gary M. Clifford, Philip Lazarus, Kjell Grankvist, Mikael Johansson, Susanne Arnold, Olle Melander, Hans Brunnström, Stefania Boccia, Gabriella Cadoni, Wim Timens, Ma'en Obeidat, Xiangjun Xiao, Richard S. Houlston, Rayjean J. Hung, Paul Brennan

Research output: Contribution to journalArticlepeer-review

13 Scopus citations

Abstract

Squamous cell carcinomas (SqCC) of the aerodigestive tract have similar etiological risk factors. Although genetic risk variants for individual cancers have been identified, an agnostic, genome-wide search for shared genetic susceptibility has not been performed. To identify novel and pleotropic SqCC risk variants, we performed a meta-analysis of GWAS data on lung SqCC (LuSqCC), oro/pharyngeal SqCC (OSqCC), laryngeal SqCC (LaSqCC) and esophageal SqCC (ESqCC) cancers, totaling 13,887 cases and 61,961 controls of European ancestry. We identified one novel genome-wide significant (Pmeta<5x10-8) aerodigestive SqCC susceptibility loci in the 2q33.1 region (rs56321285, TMEM273). Additionally, three previously unknown loci reached suggestive significance (Pmeta<5x10-7): 1q32.1 (rs12133735, near MDM4), 5q31.2 (rs13181561, TMEM173) and 19p13.11 (rs61494113, ABHD8). Multiple previously identified loci for aerodigestive SqCC also showed evidence of pleiotropy in at least another SqCC site, these include: 4q23 (ADH1B), 6p21.33 (STK19), 6p21.32 (HLA-DQB1), 9p21.33 (CDKN2B-AS1) and 13q13.1(BRCA2). Gene-based association and gene set enrichment identified a set of 48 SqCC-related genes to DNA damage and epigenetic regulation pathways. Our study highlights the importance of cross-cancer analyses to identify pleiotropic risk loci of histology-related cancers arising at distinct anatomical sites.

Original languageEnglish
Article numbere1009254
JournalPLoS Genetics
Volume17
Issue number3
DOIs
StatePublished - Mar 5 2021

Bibliographical note

Publisher Copyright:
Copyright: This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.

ASJC Scopus subject areas

  • Ecology, Evolution, Behavior and Systematics
  • Molecular Biology
  • Genetics
  • Genetics(clinical)
  • Cancer Research

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