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*

*Corresponding author for this work

Research output: Contribution to journalArticle (Academic Journal)peer-review

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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
Number of pages19
JournalPLoS Genetics
Volume17
Issue number3
Early online date5 Mar 2021
DOIs
Publication statusPublished - 5 Mar 2021

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