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

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Lesseur, C, Ferreiro-Iglesias, A, McKay, JD, Bossé, Y, Johansson, M, Gaborieau, V, Landi, MT, Christiani, DC, Caporaso, NC, Bojesen, SE et al (show 43 more authors) , Amos, CI, Shete, S, Liu, G, Rennert, G, Albanes, D, Aldrich, MC, Tardon, A, Chen, C, Triantafillos, L, Field, JK ORCID: 0000-0003-3951-6365, Teare, MD, Kiemeney, LA, Diergaarde, B, Ferris, RL, Zienolddiny, S, Lam, S, Olshan, AF, Weissler, MC, Lacko, M, Risch, A, Bickeböller, H, Ness, AR, Thomas, S, Le Marchand, L, Schabath, MB, Wünsch-Filho, V, Tajara, EH, Andrew, AS, Clifford, GM, Lazarus, P, Grankvist, K, Johansson, M, Arnold, S, Melander, O, Brunnström, H, Boccia, S, Cadoni, G, Timens, W, Obeidat, M, Xiao, X, Houlston, RS, Hung, RJ and Brennan, P (2021) Genome-wide association meta-analysis identifies pleiotropic risk loci for aerodigestive squamous cell cancers Plos Genetics, 17 (3). e1009254-. ISSN 1553-7390, 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 (P<inf>meta</inf><5x10^-8) aerodigestive SqCC susceptibility loci in the 2q33.1 region (rs56321285, TMEM273). Additionally, three previously unknown loci reached suggestive significance (P<inf>meta</inf><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.

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 & Life Sciences Faculty of Health & Life Sciences > Inst. Systems, Molec & Integrative Biology > Inst. Systems, Molec & Integrative Biology
Depositing User:	Symplectic Admin
Date Deposited:	12 Mar 2021 11:08
Last Modified:	01 Mar 2026 09:53
DOI:	10.1371/journal.pgen.1009254
Open Access URL:	https://journals.plos.org/plosgenetics/article?id=...
Related Websites:	Author Publisher
URI:	https://livrepository.liverpool.ac.uk/id/eprint/3117096
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