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

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  • Lesseur, C.
    • Other Affiliation: World Health Organization
  • Ferreiro-Iglesias, A.
    • Other Affiliation: World Health Organization
  • McKay, J.D.
    • Other Affiliation: World Health Organization
  • Bossé, Y.
    • Other Affiliation: Laval University
  • Johansson, M.
    • Other Affiliation: World Health Organization
  • Gaborieau, V.
    • Other Affiliation: World Health Organization
  • Landi, M.T.
    • Other Affiliation: National Institutes of Health
  • Christiani, D.C.
    • Other Affiliation: Massachusetts General Hospital
  • Caporaso, N.C.
    • Other Affiliation: National Institutes of Health
  • Bojesen, S.E.
    • Other Affiliation: Herlev and Gentofte Hospital
  • Amos, C.I.
    • Other Affiliation: Baylor college of Medicine
  • Shete, S.
    • Other Affiliation: The University of Texas M.D. Anderson Cancer Center
  • Liu, G.
    • Other Affiliation: University of Toronto
  • Rennert, G.
    • Other Affiliation: Carmel Medical Center
  • Albanes, D.
    • Other Affiliation: National Institutes of Health
  • Aldrich, M.C.
    • Other Affiliation: Vanderbilt University
  • Tardon, A.
    • Other Affiliation: University of Oviedo
  • Chen, C.
    • Other Affiliation: University of Washington
  • Triantafillos, L.
    • Other Affiliation: University of Liverpool
  • Field, J.K.
    • Other Affiliation: University of Liverpool
  • Teare, M.D.
    • Other Affiliation: University Of Sheffield
  • Kiemeney, L.A.
    • Other Affiliation: Radboud University Medical Center
  • Diergaarde, B.
    • Other Affiliation: University of Pittsburgh
  • Ferris, R.L.
    • Other Affiliation: University of Pittsburgh
  • Zienolddiny, S.
    • Other Affiliation: National Institute of Occupational Health
  • Lam, S.
    • Other Affiliation: British Columbia Cancer Agency
  • Olshan, A.F.
    • Affiliation: Gillings School of Global Public Health, Department of Epidemiology
  • Weissler, M.C.
    • Affiliation: School of Medicine, Department of Otolaryngology/Head and Neck Surgery
  • Lacko, M.
    • Other Affiliation: Maastricht University Medical Center
  • Risch, A.
    • Other Affiliation: University of Salzburg
  • Bickeböller, H.
    • Other Affiliation: Georg-August-University Göttingen
  • Ness, A.R.
    • Other Affiliation: University of Bristol
  • Thomas, S.
    • Other Affiliation: University of Bristol
  • Le Marchand, L.
    • Other Affiliation: University of Hawaii
  • Schabath, M.B.
    • Other Affiliation: H. Lee Moffitt Cancer Center and Research Institute
  • Wünsch-Filho, V.
    • Other Affiliation: Universidade de São Paulo
  • Tajara, E.H.
    • Other Affiliation: School of Medicine of São José do Rio Preto
  • Andrew, A.S.
    • Other Affiliation: Dartmouth College
  • Clifford, G.M.
    • Other Affiliation: World Health Organization
  • Lazarus, P.
    • Other Affiliation: Washington State University
  • Grankvist, K.
    • Other Affiliation: Umeå University
  • Johansson, M.
    • Other Affiliation: Umeå University
  • Arnold, S.
    • Other Affiliation: University of Kentucky
  • Melander, O.
    • Other Affiliation: Lund University
  • Brunnström, H.
    • Other Affiliation: Lund University
  • Boccia, S.
    • Other Affiliation: Università Cattolica del Sacro Cuore
  • Cadoni, G.
    • Other Affiliation: Università Cattolica del Sacro Cuore
  • Timens, W.
    • Other Affiliation: University of Groningen
  • Obeidat, M.
    • Other Affiliation: University of British Columbia
  • Xiao, X.
    • Other Affiliation: Baylor college of Medicine
  • Houlston, R.S.
    • Other Affiliation: The Institute of Cancer Research, London
  • Hung, R.J.
    • Other Affiliation: Sinai Health System
  • Brennan, P.
    • Other Affiliation: World Health Organization
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.
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  • Article
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  • In Copyright
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  • CC0 1.0 Universal
Journal title
  • PLoS Genetics
Journal volume
  • 17
Journal issue
  • 3
Language
  • English
Version
  • Publisher
Funder
  • National Center for Research Resources, NCRR: P20RR018787, S10RR025141
  • Sundhed og Sygdom, Det Frie Forskningsråd, FSS, DFF
  • University of Texas MD Anderson Cancer Center: RO1 DE025712-01
  • University of Pittsburgh: R01CA90731
  • Princess Margaret Hospital Foundation
  • Cancer Prevention and Research Institute of Texas, CPRIT: RP130502
  • Congressionally Directed Medical Research Programs, CDMRP
  • Roy Castle Lung Cancer Foundation, RCLCF: CA033619, CA074386, CA090578, CA092824, CA164973, CA63464
  • 26820120008i-0-26800068-1
  • H. Lee Moffitt Cancer Center and Research Institute
  • National Cancer Institute, NCI: K07CA172294, P30CA047904, P30CA076292, P30CA177558, P50CA070907, P50CA097190, P50CA119997, R01CA090731, R01CA111703, R01CA151989, R01CA176568, U01CA167462, U19CA148127, U19CA203654, UO1-CA6367307
  • Center for Clinical and Translational Science, University of Illinois at Chicago, CCTS, UIC
  • FICYT IB09-133, FICYT PB02-67
  • U.S. Department of Defense, DOD
  • Vanderbilt University Medical Center, VUMC: 1S10RR025141-01
  • National Institute of Dental and Craniofacial Research, NIDCR: 1X01HG007780-0, R01DE025712
  • National Center for Advancing Translational Sciences, NCATS: UL1TR000117, UL1TR000445
  • National Human Genome Research Institute, NHGRI: U01HG004798
  • R01 CA176568
  • Norges Forskningsråd
  • Canadian Cancer Society Research Institute, CCS: 020214
  • Kreftforeningen, NCS
  • CA148127S1, U19-CA148127
  • 09KN-15
  • Universidad de Oviedo
  • Medical Research and Materiel Command, MRMC: 10153006, W81XWH-11-1-0781
  • Canada Research Chairs: U19 CA203654
  • Overlæge Johan Boserup og Lise Boserups Legat
  • Cancer Research UK, CRUK: FIS-01/310, FIS-07-BI060604, FIS-PI03-0365
  • Fundação de Amparo à Pesquisa do Estado de São Paulo, FAPESP: 04/12054-9, 10/51168
  • National Institutes of Health, NIH
  • Herlev Hospital
ISSN
  • 1553-7390
Publisher
  • Public Library of Science

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