Journal Article

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

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

2021

Overview

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.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: 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