Genome-wide association meta-analysis identifies pleiotropic risk loci for aerodigestive squamous cell cancers
Corina Lesseur, Aida Ferreiro-Iglesias, James McKay, Yohan Bossé, Mattias Johansson, Valérie Gaborieau, Maria Teresa Landi, David C. Christiani, Neil E. Caporaso, Stig E. Bojesen, Christopher I. Amos, Sanjay Shete, Geoffrey Liu, Gad Rennert, Demetrius Albanes, Melinda C. Aldrich, Adonina Tardón, Chu Chen, Triantafillos Liloglou, John K. Field, M. 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 Ness, Steve Thomas, Loı̈c Le Marchand, Matthew B. Schabath, Victor Wünsch‐Filho, Eloíza H. Tajara, Angeline S. Andrew, Gary M. Clifford, Philip Lazarus, Kjell Grankvist, Mikael Johansson, Susanne M. Arnold, Olle Melander, Hans Brunnström, Stefania Boccia, Gabriella Cadoni, Wim Timens, Ma’en Obeidat, Xiangjun Xiao, Richard S. Houlston, Rayjean J. Hung, Paul Brennan
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.