Genome-Wide Association Meta-Analysis Identifies Pleiotropic Risk Loci for Aerodigestive Squamous Cell Cancers

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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 Egil, et al. (2021). Genome-Wide Association Meta-Analysis Identifies Pleiotropic Risk Loci for Aerodigestive Squamous Cell Cancers. PLOS Genetics, 17(3), e1009254. PMCID: PMC7968735

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 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.

URL

http://dx.doi.org/10.1371/journal.pgen.1009254

Reference Type

Journal Article

Year Published

2021

Journal Title

PLOS Genetics

Author(s)

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 Egil
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 Christian
Lacko, Martin
Risch, Angela
Bickeböller, Heike
Ness, Andrew 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 M.
Melander, Olle
Brunnström, Hans
Boccia, Stefania
Cadoni, Gabriella
Timens, Wim
Obeidat, Ma'en
Xiao, Xiangjun
Houlston, Richard S.
Hung, Rayjean J.
Brennan, Paul

Article Type

Regular

PMCID

PMC7968735

ORCiD

Olshan - 0000-0001-9115-5128