TY - JOUR
T1 - Genome-wide association meta-analysis identifies pleiotropic risk loci for aerodigestive squamous cell cancers
AU - Lesseur, Corina
AU - Ferreiro-Iglesias, Aida
AU - McKay, James D.
AU - Bossé, Yohan
AU - Johansson, Mattias
AU - Gaborieau, Valerie
AU - Landi, Maria Teresa
AU - Christiani, David C.
AU - Caporaso, Neil C.
AU - Bojesen, Stig E.
AU - Amos, Christopher I.
AU - Shete, Sanjay
AU - Liu, Geoffrey
AU - Rennert, Gadi
AU - Albanes, Demetrios
AU - Aldrich, Melinda C.
AU - Tardon, Adonina
AU - Chen, Chu
AU - Triantafillos, Liloglou
AU - Field, John K.
AU - Teare, Marion Dawn
AU - Kiemeney, Lambertus A.
AU - Diergaarde, Brenda
AU - Ferris, Robert L.
AU - Zienolddiny, Shanbeh
AU - Lam, Stephen
AU - Olshan, Andrew F.
AU - Weissler, Mark C.
AU - Lacko, Martin
AU - Risch, Angela
AU - Bickeböller, Heike
AU - Ness, Andy R.
AU - Thomas, Steve
AU - Le Marchand, Loic
AU - Schabath, Matthew B.
AU - Wünsch-Filho, Victor
AU - Tajara, Eloiza H.
AU - Andrew, Angeline S.
AU - Clifford, Gary M.
AU - Lazarus, Philip
AU - Grankvist, Kjell
AU - Johansson, Mikael
AU - Arnold, Susanne
AU - Melander, Olle
AU - Brunnström, Hans
AU - Boccia, Stefania
AU - Cadoni, Gabriella
AU - Timens, Wim
AU - Obeidat, Ma'en
AU - Xiao, Xiangjun
N1 - Funding Information:
The TRICL-ILCCO OncoArray was supported by the Centre for Inherited Disease Research (26820120008i-0-26800068-1). Genotyping for the oral and oropharyngeal cancer OncoArray was funded through the U.S. National Institute of Dental and Craniofacial Research (NIDCR) grant 1X01HG007780-0. The Transdisciplinary Research for Cancer in Lung (TRICL) of the International Lung Cancer Consortium (ILCCO) was supported by grants U19-CA148127 and CA148127S1 and more recently by the INTEGRAL grant U19CA203654. ILCCO data harmonization is supported by the Canada Research Chair to R.J.H. and U19 CA203654. The work of the Houlston Laboratory is funded by Cancer Research UK. The CAPUA study was supported by FIS-FEDER/Spain grant numbers FIS-01/310, FIS-PI03-0365, and FIS-07-BI060604, FICYT/Asturias grant numbers FICYT PB02-67 and FICYT IB09-133, and the University Institute of Oncology (IUOPA), of the University of Oviedo and the Ciber de Epidemiologia y Salud P?blica. CIBERESP, SPAIN. The work performed in the CARET study was supported by the National Institute of Health /National Cancer Institute: UM1 CA167462 (PI: Goodman), National Institute of Health UO1-CA6367307 (PIs Omen, Goodman); National Institute of Health R01 CA111703 (PI Chen), National Institute of Health 5R01 CA151989-01A1(PI Doherty). The Liverpool Lung project is supported by the Roy Castle Lung Cancer Foundation. The Harvard Lung Cancer Study was supported by the NIH (National Cancer Institute) grants CA092824, CA090578, CA074386. The Multiethnic Cohort Study was partially supported by NIH Grants CA164973, CA033619, CA63464 and CA148127. The work performed in MSH-PMH study was supported by The Canadian Cancer Society Research Institute (020214), Ontario Institute of Cancer and Cancer Care Ontario Chair Award to R.J.H. and G.L. and the Alan Brown Chair and Lusi Wong Programs at the Princess Margaret Hospital Foundation. The Norway study was supported by Norwegian Cancer Society, Norwegian Research Council. The work in TLC study has been supported in part the James & Esther King Biomedical Research Program (09KN-15), National Institutes of Health Specialized Programs of Research Excellence (SPORE) Grant (P50 CA119997), and by a Cancer Center Support Grant (CCSG) at the H. Lee Moffitt Cancer Center and Research Institute, an NCI designated Comprehensive Cancer Center (grant number P30-CA76292).The Vanderbilt Lung Cancer Study ? BioVU dataset used for the analyses described was obtained from Vanderbilt University Medical Center?s BioVU, which is supported by institutional funding, the 1S10RR025141-01 instrumentation award, and by the Vanderbilt CTSA grant UL1TR000445 from NCATS/NIH. Dr. Aldrich was supported by NIH/National Cancer Institute K07CA172294 (PI: Aldrich) and Dr. Bush was supported by NHGRI/NIH U01HG004798 (PI: Crawford). The Copenhagen General Population Study (CGPS) was supported by the Chief Physician Johan Boserup and Lise Boserup Fund, the Danish Medical Research Council and Herlev Hospital. The NELCS study: Grant Number P20RR018787 from the National Center for Research Resources (NCRR), a component of the National Institutes of Health (NIH). The Kentucky Lung Cancer Research Initiative was supported by the Department of Defense [Congressionally Directed Medical Research Program, U.S. Army Medical Research and Materiel Command Program] under award number: 10153006 (W81XWH-11-1-0781). Views and opinions of, and endorsements by the author(s) do not reflect those of the US Army or the Department of Defense. This research was also supported by unrestricted infrastructure funds from the UK Center for Clinical and Translational Science, NIH grant UL1TR000117 and Markey Cancer Center NCI Cancer Center Support Grant (P30CA177558) Shared Resource Facilities: Cancer Research Informatics, Biospecimen and Tissue Procurement, and Biostatistics and Bioinformatics. The M.D. Anderson Cancer Center study was supported in part by grants from the NIH (P50CA070907, R01 CA176568) (to X. Wu), Cancer Prevention & Research Institute of Texas (RP130502) (to X. Wu), and The University of Texas MD Anderson Cancer Center institutional support for the Center for Translational and Public Health Genomics. Head and Neck studies included in the VOYAGER consortium were supported by NIDCR RO1 DE025712-01. The University of Pittsburgh head and neck cancer case?control study is supported by US National Institutes of Health grants P50CA097190 and P30CA047904. The Carolina Head and Neck Cancer Study (CHANCE) was supported by the National Cancer Institute (R01CA90731). The Head and Neck Genome Project (GENCAPO) was supported by the Funda??o de Amparo ? Pesquisa do Estado de S?o Paulo (FAPESP; grants 04/12054-9 and 10/51168-
Publisher Copyright:
Copyright: This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.
PY - 2021/3/5
Y1 - 2021/3/5
N2 - 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.
AB - 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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U2 - 10.1371/journal.pgen.1009254
DO - 10.1371/journal.pgen.1009254
M3 - Article
C2 - 33667223
AN - SCOPUS:85102647478
SN - 1553-7390
VL - 17
JO - PLoS Genetics
JF - PLoS Genetics
IS - 3
M1 - e1009254
ER -