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.

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Published in PLOS Genetics, v. 17, issue 3, e1009254.

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.

Due to the large number of authors, only the first 20 authors and the author affiliated with the University of Kentucky are listed in the author section above. For the complete list of authors, please download this article or visit: https://doi.org/10.1371/journal.pgen.1009254

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The INTEGRAL-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 Integrative Analysis of Lung Cancer Risk and (INTEGRAL) 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. C.I.A. is a Research Scholar of the Cancer Prevention Institute of Texas and supported by RR170048. 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 Pública. 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 Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP; grants 04/12054-9 and 10/51168-0). The authors thank all the members of the GENCAPO team. The HN5000 study was funded by the National Institute for Health Research (NIHR) under its Programme Grants for Applied Research scheme (RP-PG-0707-10034); the views expressed in this publication are those of the author(s) and not necessarily those of the NHS, the NIHR or the UK Department of Health. The Toronto study was funded by the Canadian Cancer Society Research Institute (020214) and the National Cancer Institute (U19CA148127) and by the Cancer Care Ontario Research Chair. The Rome Study was supported by the Associazione Italiana per la Ricerca sul Cancro (AIRC). The Alcohol-Related Cancers and Genetic Susceptibility Study in Europe (ARCAGE) was funded by the European Commission’s fifth framework programme (QLK1-2001-00182), the Italian Association for Cancer Research, Compagnia di San Paolo/FIRMS, Region Piemonte and Padova University (CPDA057222).

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Genotype data have been deposited dbGaP accession number phs001202.v1.p1 for the oral and pharyngeal study [17] and for the lung data [16] accession numbers phs001273.v3.p2 and phs000876.v2.p1. The summary statistics for the lung squamous dataset are deposited in dbGaP (phs001273.v3.p2). The oral and pharyngeal GWAS summary statistics by cancer site and world region have been deposited in the IEU Open GWAS platform (https://gwas.mrcieu.ac.uk/) under the GWAs IDs: ieu-b-89, ieu-b-90, ieu-b-94, ieu-b-96, ieu-b-93, ieu-b-97, ieu-b-91, ieu-b-95 and 98.

pgen.1009254.s001.tiff (2966 kB)
S1 Fig. SqCC F-E meta-analyses. https://doi.org/10.1371/journal.pgen.1009254.s001

pgen.1009254.s002.tif (392 kB)
S2 Fig. Regional association plot at 2q33.1. https://doi.org/10.1371/journal.pgen.1009254.s002

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S3 Fig. Regional association plot at 1q32.1. https://doi.org/10.1371/journal.pgen.1009254.s003

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S4 Fig. rs12133735 MDM4 lung eQTL.. https://doi.org/10.1371/journal.pgen.1009254.s004

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S5 Fig. Regional association plot at 5q31.2. https://doi.org/10.1371/journal.pgen.1009254.s005

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S6 Fig. Regional association plot at 19p13.11. https://doi.org/10.1371/journal.pgen.1009254.s006

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S7 Fig. Regional association plot at 6p22.1- 6p21.33. https://doi.org/10.1371/journal.pgen.1009254.s007

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S8 Fig. Regional association plot at 9p21.3. https://doi.org/10.1371/journal.pgen.1009254.s008

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S9 Fig. Regional association plot at 15p25.1. https://doi.org/10.1371/journal.pgen.1009254.s009

pgen.1009254.s010.xlsx (1688 kB)
S1 Table. Results with P<5x10-5 aerodigestive SqCC meta-analyses. https://doi.org/10.1371/journal.pgen.1009254.s010

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S2 Table. Pleiotropic aerodigestive SqCC risk variants. https://doi.org/10.1371/journal.pgen.1009254.s011

pgen.1009254.s012.xlsx (10 kB)
S3 Table. Lung Cis-eQTLs for aerodigestive SqCC loci. https://doi.org/10.1371/journal.pgen.1009254.s012

pgen.1009254.s013.xlsx (10 kB)
S4 Table. Cis-eQTLs and cis-sQTLs for new SqCC loci. https://doi.org/10.1371/journal.pgen.1009254.s013

pgen.1009254.s014.xlsx (9 kB)
S5 Table. Chromatin states and histone marks in lung and esophageal tissues or cells for new SqCC loci. https://doi.org/10.1371/journal.pgen.1009254.s014

pgen.1009254.s015.xlsx (12 kB)
S6 Table. Summary of reported cancer risk associations within the newly SqCC risk loci. https://doi.org/10.1371/journal.pgen.1009254.s015

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S7 Table. Aerodigestive loci genes with somatic mutations. https://doi.org/10.1371/journal.pgen.1009254.s016

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S8 Table. Significant results from the gene-based aerodigestive SqCC associations. https://doi.org/10.1371/journal.pgen.1009254.s017

pgen.1009254.s018.xlsx (31 kB)
S9 Table. Aerodigestive SqCC results from the FUMA SNPs to genes mapping. https://doi.org/10.1371/journal.pgen.1009254.s018

pgen.1009254.s019.xlsx (11 kB)
S10 Table. Genes overlapping between FUMA and MAGMA analyses. https://doi.org/10.1371/journal.pgen.1009254.s019

pgen.1009254.s020.xlsx (15 kB)
S11 Table. Aerodigestive SqCC results from gene set enrichment analyses. https://doi.org/10.1371/journal.pgen.1009254.s020