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

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 SqC...

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Published in:	PLoS genetics Vol. 17; no. 3; p. e1009254
Main Authors:	Lesseur, Corina, Ferreiro-Iglesias, Aida, McKay, James D., Bossé, Yohan, Johansson, Mattias, Gaborieau, Valerie, Landi, Maria Teresa, Christiani, David C., Caporaso, Neil C., Bojesen, Stig E., Amos, Christopher I., Shete, Sanjay, Liu, Geoffrey, Rennert, Gadi, Albanes, Demetrius, Aldrich, Melinda C., Tardon, Adonina, Chen, Chu, Triantafillos, Liloglou, Field, John K., 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, Bickeböller, Heike, Ness, Andy R., Thomas, Steve, Le Marchand, Loic, Schabath, Matthew B., Wünsch-Filho, Victor, Tajara, Eloiza H., Andrew, Angeline S., Clifford, Gary M., Lazarus, Philip, Grankvist, Kjell, Johansson, Mikael, Arnold, Susanne, Melander, Olle, Brunnström, Hans, Boccia, Stefania, Cadoni, Gabriella, Timens, Wim, Obeidat, Ma’en, Xiao, Xiangjun, Houlston, Richard S., Hung, Rayjean J., Brennan, Paul
Format:	Journal Article
Language:	English
Published:	United States Public Library of Science 05.03.2021 Public Library of Science (PLoS)
Subjects:	Alleles Association analysis Biology and Life Sciences Biomarkers, Tumor Breast Cancer and Oncology Cancer och onkologi Carcinoma, Squamous Cell - genetics Carcinoma, Squamous Cell - metabolism Carcinoma, Squamous Cell - pathology Clinical Medicine Copy number Correlation analysis Datasets Deoxyribonucleic acid Digestive system cancer Digestive System Neoplasms - genetics Digestive System Neoplasms - metabolism Digestive System Neoplasms - pathology DNA DNA methylation Esophageal cancer Esophagus Gene expression Gene loci Genetic analysis Genetic aspects Genetic Loci Genetic Predisposition to Disease Genome-wide association studies Genome-Wide Association Study Genomes Genomic analysis Genotype Head & neck cancer Head and neck cancer Human papillomavirus Humans Klinisk medicin Larynx Lung cancer Lung carcinoma Medical and Health Sciences Medicin och hälsovetenskap Medicine and Health Sciences Meta-analysis Mutation Odds Ratio Ovarian cancer Pharynx Physical Sciences Prostate cancer Research and Analysis Methods Risk factors Signal Transduction Solid tumors Squamous cell carcinoma Tobacco smoking Tumors France
ISSN:	1553-7404, 1553-7390, 1553-7404
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Summary:	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 meta <5x10 -8 ) aerodigestive SqCC susceptibility loci in the 2q33.1 region (rs56321285, TMEM273 ). Additionally, three previously unknown loci reached suggestive significance ( P meta <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.
Bibliography:	new_version ObjectType-Article-2 SourceType-Scholarly Journals-1 content type line 14 ObjectType-Feature-3 ObjectType-Evidence Based Healthcare-1 ObjectType-Article-1 ObjectType-Feature-2 content type line 23 I have read the journal’s policy and the authors of this manuscript have the following competing interests. Dr. Ferris has the following financial disclosures: Aduro Biotech, Inc (consulting); Astra-Zeneca/MedImmune (clinical trial, research funding); Bristol-Myers Squibb (advisory board, clinical trial, research funding); EMD Serono (advisory board); MacroGenics, Inc (advisory board); Merck (advisory board, clinical trial); Novasenta (consulting, stock, research funding); Numab Therapeutics AG (advisory board); Pfizer (advisory board); Sanofi (consultant); Tesaro (research funding) and Zymeworks, Inc (consultant). All other authors have no conflicts to disclose.
ISSN:	1553-7404 1553-7390 1553-7404
DOI:	10.1371/journal.pgen.1009254