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

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Lesseur, Corina, Ferreiro-Iglesias, Aida, McKay, James D, Bosse, Yohan, Johansson, Mattias, Gaborieau, Valerie, Landi, Maria Teresa, Christiani, David C, Caporaso, Neil C, Bojesen, Stig E et al (show 43 more authors) , Amos, Christopher I, Shete, Sanjay, Liu, Geoffrey, Rennert, Gadi, Albanes, Demetrios, Aldrich, Melinda C, Tardon, Adonina, Chen, Chu, Triantafillos, Liloglou, Field, John K ORCID: 0000-0003-3951-6365, Teare, Marion Dawn, Kiemeney, Lambertus A, Diergaarde, Brenda, Ferris, Robert L, Zienolddiny, Shanbeh, Lam, Stephen, Olshan, Andrew F, Weissler, Mark C, Lacko, Martin, Risch, Angela, Bickeboller, Heike, Ness, Andy R, Thomas, Steve, Le Marchand, Loic, Schabath, Matthew B, Wunsch-Filho, Victor, Tajara, Eloiza H, Andrew, Angeline S, Clifford, Gary M, Lazarus, Philip, Grankvist, Kjell, Johansson, Mikael, Arnold, Susanne, Melander, Olle, Brunnstrom, Hans, Boccia, Stefania, Cadoni, Gabriella, Timens, Wim, Obeidat, Ma'en, Xiao, Xiangjun, Houlston, Richard S, Hung, Rayjean J and Brennan, Paul (2021) Genome-wide association meta-analysis identifies pleiotropic risk loci for aerodigestive squamous cell cancers. PLOS GENETICS, 17 (3). e1009254-. ISSN 1553-7404, 1553-7404

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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 rel 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.

Item Type:	Article
Uncontrolled Keywords:	Humans, Carcinoma, Squamous Cell, Digestive System Neoplasms, Genetic Predisposition to Disease, Odds Ratio, Signal Transduction, Genotype, Alleles, Genome-Wide Association Study, Genetic Loci, Biomarkers, Tumor
Divisions:	Faculty of Health and Life Sciences Faculty of Health and Life Sciences > Institute of Systems, Molecular and Integrative Biology
Depositing User:	Symplectic Admin
Date Deposited:	12 Mar 2021 11:08
Last Modified:	07 Dec 2024 21:09
DOI:	10.1371/journal.pgen.1009254
Open Access URL:	https://journals.plos.org/plosgenetics/article?id=...
Related URLs:	Author Publisher
URI:	https://livrepository.liverpool.ac.uk/id/eprint/3117096