PLoS Genetics (Mar 2021)

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

  • Corina Lesseur,
  • Aida Ferreiro-Iglesias,
  • James D McKay,
  • Yohan Bossé,
  • Mattias Johansson,
  • Valerie Gaborieau,
  • Maria Teresa Landi,
  • David C Christiani,
  • Neil C Caporaso,
  • Stig E Bojesen,
  • Christopher I Amos,
  • Sanjay Shete,
  • Geoffrey Liu,
  • Gadi Rennert,
  • Demetrius Albanes,
  • Melinda C Aldrich,
  • Adonina Tardon,
  • Chu Chen,
  • Liloglou Triantafillos,
  • John K Field,
  • Marion 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 R Ness,
  • Steve Thomas,
  • Loic Le Marchand,
  • Matthew B Schabath,
  • Victor Wünsch-Filho,
  • Eloiza H Tajara,
  • Angeline S Andrew,
  • Gary M Clifford,
  • Philip Lazarus,
  • Kjell Grankvist,
  • Mikael Johansson,
  • Susanne Arnold,
  • Olle Melander,
  • Hans Brunnström,
  • Stefania Boccia,
  • Gabriella Cadoni,
  • Wim Timens,
  • Ma'en Obeidat,
  • Xiangjun Xiao,
  • Richard S Houlston,
  • Rayjean J Hung,
  • Paul Brennan

DOI
https://doi.org/10.1371/journal.pgen.1009254
Journal volume & issue
Vol. 17, no. 3
p. e1009254

Abstract

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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.