We conducted a genome-wide association study of oral cavity and pharyngeal cancer in 6,034 cases and 6,585 controls from Europe, North America and South America. We detected eight significantly associated loci (P < 5 × 10−8), seven of which are new for these cancer sites. Oral and pharyngeal cancers combined were associated with loci at 6p21.32 (rs3828805, HLA-DQB1), 10q26.13 (rs201982221, LHPP) and 11p15.4 (rs1453414, OR52N2TRIM5). Oral cancer was associated with two new regions, 2p23.3 (rs6547741, GPN1) and 9q34.12 (rs928674, LAMC3), and with known cancer-related loci—9p21.3 (rs8181047, CDKN2B-AS1) and 5p15.33 (rs10462706, CLPTM1L). Oropharyngeal cancer associations were limited to the human leukocyte antigen (HLA) region, and classical HLA allele imputation showed a protective association with the class II haplotype HLA-DRB1*1301–HLA-DQA1*0103–HLA-DQB1*0603 (odds ratio (OR) = 0.59, P = 2.7 × 10−9). Stratified analyses on a subgroup of oropharyngeal cases with information available on human papillomavirus (HPV) status indicated that this association was considerably stronger in HPV-positive (OR = 0.23, P = 1.6 × 10−6) than in HPV-negative (OR = 0.75, P = 0.16) cancers.

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  1. 1.

    , , & Epidemiology of human papillomavirus–positive head and neck squamous cell carcinoma. J. Clin. Oncol. 33, 3235–3242 (2015).

  2. 2.

    et al. Human papillomavirus and rising oropharyngeal cancer incidence in the United States. J. Clin. Oncol. 29, 4294–4301 (2011).

  3. 3.

    , , & Human papillomavirus types in head and neck squamous cell carcinomas worldwide: a systematic review. Cancer Epidemiol. Biomarkers Prev. 14, 467–475 (2005).

  4. 4.

    et al. Low human papillomavirus prevalence in head and neck cancer: results from two large case–control studies in high-incidence regions. Int. J. Epidemiol. 40, 489–502 (2011).

  5. 5.

    et al. Human papillomavirus (HPV) 16 and the prognosis of head and neck cancer in a geographical region with a low prevalence of HPV infection. Cancer Causes Control 25, 461–471 (2014).

  6. 6.

    et al. Multiple ADH genes are associated with upper aerodigestive cancers. Nat. Genet. 40, 707–709 (2008).

  7. 7.

    et al. A genome-wide association study of upper aerodigestive tract cancers conducted within the INHANCE consortium. PLoS Genet. 7, e1001333 (2011).

  8. 8.

    et al. A reference panel of 64,976 haplotypes for genotype imputation. Nat. Genet. 48, 1279–1283 (2016).

  9. 9.

    et al. Practical aspects of imputation-driven meta-analysis of genome-wide association studies. Hum. Mol. Genet. 17R2, R122–R128 (2008).

  10. 10.

    et al. Evidence for an important role of alcohol- and aldehyde-metabolizing genes in cancers of the upper aerodigestive tract. Cancer Epidemiol. Biomarkers Prev. 15, 696–703 (2006).

  11. 11.

    , & The role of alcohol dehydrogenase genes in head and neck cancers: a systematic review and meta-analysis of ADH1B and ADH1C. Mutagenesis 27, 275–286 (2012).

  12. 12.

    et al. Genetic variability in the regulation of gene expression in ten regions of the human brain. Nat. Neurosci. 17, 1418–1428 (2014).

  13. 13.

    & Human GTPases associate with RNA polymerase II to mediate its nuclear import. Mol. Cell. Biol. 31, 3953–3962 (2011).

  14. 14.

    GTEx Consortium. The Genotype-Tissue Expression (GTEx) pilot analysis: multitissue gene regulation in humans. Science 348, 648–660 (2015).

  15. 15.

    et al. Lung cancer susceptibility locus at 5p15.33. Nat. Genet. 40, 1404–1406 (2008).

  16. 16.

    et al. Common 5p15.33 and 6p21.33 variants influence lung cancer risk. Nat. Genet. 40, 1407–1409 (2008).

  17. 17.

    et al. Sequence variants at the TERTCLPTM1L locus associate with many cancer types. Nat. Genet. 41, 221–227 (2009).

  18. 18.

    et al. New common variants affecting susceptibility to basal cell carcinoma. Nat. Genet. 41, 909–914 (2009).

  19. 19.

    et al. TERTCLPTM1L rs401681 C>T polymorphism was associated with a decreased risk of esophageal cancer in a Chinese population. PLoS One 9, e100667 (2014).

  20. 20.

    et al. A genome-wide association study identifies pancreatic cancer susceptibility loci on chromosomes 13q22.1, 1q32.1 and 5p15.33. Nat. Genet. 42, 224–228 (2010).

  21. 21.

    et al. A GWAS meta-analysis and replication study identifies a novel locus within CLPTM1L/TERT associated with nasopharyngeal carcinoma in individuals of Chinese ancestry. Cancer Epidemiol. Biomarkers Prev. 25, 188–192 (2016).

  22. 22.

    et al. Genome-wide meta-analysis identifies five new susceptibility loci for cutaneous malignant melanoma. Nat. Genet. 47, 987–995 (2015).

  23. 23.

    et al. Genome-wide association study identifies five susceptibility loci for glioma. Nat. Genet. 41, 899–904 (2009).

  24. 24.

    et al. Genome-wide association study identifies five new breast cancer susceptibility loci. Nat. Genet. 42, 504–507 (2010).

  25. 25.

    et al. Influence of common genetic variation on lung cancer risk: meta-analysis of 14 900 cases and 29 485 controls. Hum. Mol. Genet. 21, 4980–4995 (2012).

  26. 26.

    et al. A genome-wide association study of nasopharyngeal carcinoma identifies three new susceptibility loci. Nat. Genet. 42, 599–603 (2010).

  27. 27.

    et al. Joint analysis of three genome-wide association studies of esophageal squamous cell carcinoma in Chinese populations. Nat. Genet. 46, 1001–1006 (2014).

  28. 28.

    Cancer Genome Atlas Network. Comprehensive genomic characterization of head and neck squamous cell carcinomas. Nature 517, 576–582 (2015).

  29. 29.

    et al. Recessive LAMC3 mutations cause malformations of occipital cortical development. Nat. Genet. 43, 590–594 (2011).

  30. 30.

    et al. Genome-wide association study of susceptibility loci for cervical cancer. J. Natl. Cancer Inst. 105, 624–633 (2013).

  31. 31.

    et al. A review of human carcinogens—Part B: biological agents. Lancet Oncol. 10, 321–322 (2009).

  32. 32.

    , & Targeting the MHC class II antigen presentation pathway in cancer immunotherapy. OncoImmunology 1, 908–916 (2012).

  33. 33.

    Anonymous. Consortium launches genotyping effort. Cancer Discov. 3, 1321–1322 (2013).

  34. 34.

    et al. Principal components analysis corrects for stratification in genome-wide association studies. Nat. Genet. 38, 904–909 (2006).

  35. 35.

    , & Inference of population structure using multilocus genotype data: linked loci and correlated allele frequencies. Genetics 164, 1567–1587 (2003).

  36. 36.

    et al. Next-generation genotype imputation service and methods. Nat. Genet. 48, 1284–1287 (2016).

  37. 37.

    , & A linear complexity phasing method for thousands of genomes. Nat. Methods 9, 179–181 (2011).

  38. 38.

    , & minimac2: faster genotype imputation. Bioinformatics 31, 782–784 (2015).

  39. 39.

    et al. PLINK: a tool set for whole-genome association and population-based linkage analyses. Am. J. Hum. Genet. 81, 559–575 (2007).

  40. 40.

    et al. Imputing amino acid polymorphisms in human leukocyte antigens. PLoS One 8, e64683 (2013).

  41. 41.

    & HaploReg: a resource for exploring chromatin states, conservation, and regulatory motif alterations within sets of genetically linked variants. Nucleic Acids Res. 40, D930–D934 (2012).

  42. 42.

    qqman: an R package for visualizing GWAS results using Q–Q and Manhattan plots. Preprint at bioRxiv (2014).

  43. 43.

    Conducting meta-analyses in R with the metafor package. J. Stat. Softw. 36, 48 (2010).

  44. 44.

    et al. LocusZoom: regional visualization of genome-wide association scan results. Bioinformatics 26, 2336–2337 (2010).

  45. 45.

    & LDlink: a web-based application for exploring population-specific haplotype structure and linking correlated alleles of possible functional variants. Bioinformatics 31, 3555–3557 (2015).

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Genotyping performed at the Center for Inherited Disease Research (CIDR) was funded through US National Institute of Dental and Craniofacial Research (NIDCR) grant 1X01HG007780-0. Genotyping for shared controls with the Lung OncoArray initiative was funded through grant X01HG007492-0. C.L. undertook this work during the tenure of a postdoctoral fellowship awarded by the International Agency for Research on Cancer. The funders did not participate in study design, data collection and analysis, decision to publish or preparation of the manuscript. We acknowledge all of the participants involved in this research and the funders and support. We thank L. Fernandez for her contribution to the IARC ORC multicenter study. We are also grateful to S. Koifman for his contribution to the IARC Latin America multicenter study (S. Koifman passed away in May 2014) and to X. Castellsagué who recently passed away (June 2016).

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 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). The Rome Study was supported by the Associazione Italiana per la Ricerca sul Cancro (AIRC) awards IG 2011 10491 and IG 2013 14220 to S.B. and by Fondazione Veronesi to S.B. The IARC Latin American study was funded by the European Commission INCO-DC programme (IC18-CT97-0222), with additional funding from Fondo para la Investigación Científica y Tecnológica (Argentina) and the Fundação de Amparo à Pesquisa do Estado de São Paulo (01/01768-2). The IARC Central Europe study was supported by the European Commission's INCO-COPERNICUS Program (IC15-CT98-0332), US NIH/National Cancer Institute grant CA92039 and World Cancer Research Foundation grant WCRF 99A28.The IARC Oral Cancer Multicenter study was funded by grant S06 96 202489 05F02 from Europe against Cancer; grants FIS 97/0024, FIS 97/0662 and BAE 01/5013 from Fondo de Investigaciones Sanitarias, Spain; the UICC Yamagiwa-Yoshida Memorial International Cancer Study; the National Cancer Institute of Canada; Associazione Italiana per la Ricerca sul Cancro; and the Pan-American Health Organization. Coordination of the EPIC study is financially supported by the European Commission (DG SANCO) and the International Agency for Research on Cancer.

Author information

Author notes

    • Xavier Castellsagué



  1. International Agency for Research on Cancer (IARC/WHO), Lyon, France.

    • Corina Lesseur
    • , Silvia Franceschi
    • , Mattias Johansson
    • , Ariana Znaor
    • , Rolando Herrero
    • , Valérie Gaborieau
    • , Amélie Chabrier
    • , Devasena Anantharaman
    • , James D McKay
    •  & Paul Brennan
  2. Department of Epidemiology, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.

    • Brenda Diergaarde
  3. University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania, USA.

    • Brenda Diergaarde
  4. Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.

    • Andrew F Olshan
  5. UNC Lineberger Comprehensive Cancer Center, Chapel Hill, North Carolina, USA.

    • Andrew F Olshan
  6. Faculdade de Saúde Pública, Universidade de São Paulo, São Paulo, Brazil.

    • Victor Wünsch-Filho
  7. National Institute for Health Research (NIHR) Biomedical Research Unit in Nutrition, Diet and Lifestyle at the University Hospitals Bristol NHS Foundation Trust and the University of Bristol, Bristol, UK.

    • Andrew R Ness
  8. School of Oral and Dental Sciences, University of Bristol, Bristol, UK.

    • Andrew R Ness
    •  & Steve Thomas
  9. Princess Margaret Cancer Centre, Toronto, Ontario, Canada.

    • Geoffrey Liu
  10. Department of Otorhinolaryngology, Head and Neck Surgery, Maastricht University Medical Center, Maastricht, the Netherlands.

    • Martin Lacko
  11. Departamento de Medicina Preventiva, Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil.

    • José Eluf-Neto
  12. Department of Hygiene, Epidemiology and Medical Statistics, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece.

    • Pagona Lagiou
  13. School of Medicine, Medical Sciences and Nutrition, University of Aberdeen, Aberdeen, UK.

    • Gary J Macfarlane
  14. Department of Medical Sciences, University of Turin, Turin, Italy.

    • Lorenzo Richiardi
  15. Section of Hygiene, Institute of Public Health, Università Cattolica del Sacro Cuore, Fondazione Policlinico 'Agostino Gemelli', Rome, Italy.

    • Stefania Boccia
  16. Unit of Cancer Epidemiology, CRO Aviano National Cancer Institute, Aviano, Italy.

    • Jerry Polesel
  17. Cancer Registry of Norway, Oslo, Norway.

    • Kristina Kjaerheim
  18. Department of Cancer Epidemiology and Prevention, Institute of Carcinogenesis, N.N. Blokhin Russian Cancer Research Centre of the Russian Ministry of Health, Moscow, Russian Federation.

    • David Zaridze
    •  & Oxana Shangina
  19. Programa de Pós-Graduacão em Epidemiologia, Universidade Federal de Pelotas (UFPel), Pelotas, Brazil.

    • Ana M Menezes
  20. Epidemiology, International Center for Research (CIPE), A.C. Camargo Cancer Center, Sao Paulo, Brazil.

    • Maria Paula Curado
  21. Centre for Oral Health Research, Newcastle University, Newcastle, UK.

    • Max Robinson
  22. Leibniz Institute for Prevention Research and Epidemiology – BIPS, Bremen, Germany.

    • Wolfgang Ahrens
  23. Deparment of Molecular Medicine, University of Padova, Padova, Italy.

    • Cristina Canova
  24. Croatian National Institute of Public Health, Zagreb, Croatia.

    • Ariana Znaor
  25. Institut Català d'Oncologia (ICO)–IDIBELL, CIBERESP, l'Hospitalet de Llobregat, Barcelona, Spain.

    • Xavier Castellsagué
  26. School of Medicine, Dentistry and Nursing, University of Glasgow, Glasgow, UK.

    • David I Conway
  27. NHS National Services Scotland (NSS), Edinburgh, UK.

    • David I Conway
  28. Institute of Hygiene and Epidemiology, 1st Faculty of Medicine, Charles University, Prague, Czech Republic.

    • Ivana Holcátová
  29. National Institute of Public Health, Bucharest, Romania.

    • Dana Mates
  30. Instituto de Oncología 'Angel H. Roffo', Universidad de Buenos Aires, Buenos Aires, Argentina.

    • Marta Vilensky
  31. Trinity College School of Dental Science, Dublin, Ireland.

    • Claire M Healy
  32. Department of Environmental Epidemiology, Nofer Institute of Occupational Medicine, Lodz, Poland.

    • Neonila Szeszenia-Dąbrowska
  33. Regional Authority of Public Health, Banská Bystrica, Slovakia.

    • Eleonóra Fabiánová
  34. Maria Skłodowska-Curie Memorial Cancer Centre and Institute of Oncology (MCMCC), Warsaw, Poland.

    • Jolanta Lissowska
  35. Department of Otolaryngology–Head and Neck Surgery, University of California at San Francisco, San Francisco, California, USA.

    • Jennifer R Grandis
  36. Clinical Translational Science Institute, University of California at San Francisco, San Francisco, California, USA.

    • Jennifer R Grandis
  37. Department of Otolaryngology/Head and Neck Surgery, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.

    • Mark C Weissler
  38. Department of Molecular Biology, School of Medicine of São José do Rio Preto, São José do Rio Preto, Brazil.

    • Eloiza H Tajara
  39. Department of Stomatology, School of Dentistry, University of São Paulo, São Paulo, Brazil.

    • Fabio D Nunes
  40. Department of Head and Neck Surgery, Heliópolis Hospital, São Paulo, Brazil.

    • Marcos B de Carvalho
  41. Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada.

    • Rayjean J Hung
  42. Department of Gastroenterology, Radboud University Nijmegen Medical Center, Nijmegen, the Netherlands.

    • Wilbert H M Peters
  43. Institute of Otorhinolaryngology, Università Cattolica del Sacro Cuore, Fondazione Policlinico 'Agostino Gemelli', Rome, Italy.

    • Gabriella Cadoni
  44. Department for Determinants of Chronic Diseases (DCD), National Institute for Public Health and the Environment (RIVM), Bilthoven, the Netherlands.

    • H Bas Bueno-de-Mesquita
  45. Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, UK.

    • H Bas Bueno-de-Mesquita
  46. Department of Social and Preventive Medicine, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia.

    • H Bas Bueno-de-Mesquita
  47. German Institute of Human Nutrition in Potsdam-Rehbruecke (DIfE), Nuthetal, Germany.

    • Annika Steffen
  48. Unit of Nutrition and Cancer, Cancer Epidemiology Research Program, Institut Català d'Oncologia (ICO)–IDIBELL, l'Hospitalet de Llobregat, Barcelona, Spain.

    • Antonio Agudo
  49. Department of Biomedical Data Sciences, Geisel School of Medicine at Dartmouth, Lebanon, New Hampshire, USA.

    • Xiangjun Xiao
    •  & Christopher I Amos
  50. Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA.

    • Paolo Boffetta


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P. Brennan and J.D.M. conceived and designed the project. C.L. undertook data harmonization, genotypes quality control, GWAS analysis, imputation and meta-analyses. X.X. performed genotype calling. V.G. and A.C. organized and supervised sample selection and DNA shipments at the International Agency for Research on Cancer. A.C. performed replication TaqMan genotyping. C.L. and V.G. analyzed data from replication genotyping. C.L. and P. Brennan drafted the first version of the manuscript. B.D., A.F.O., V.W.-F., A.R.N., G.L., M.L., J.E.-N., S.F., P.L., G.J.M., L.R., S.B., J.P., K.K., D.Z., M.J., A.M.M., M.P.C., M.R., W.A., C.C., A.Z., X.C., D.I.C., I.H., D.M., M.V., C.M.H., N.S.-D., E.F., J.L., J.R.G., M.C.W., E.H.T., F.D.N., M.B.d.C., S.T., R.J.H., W.H.M.P., R.H., G.C., A.S., A.A., O.S., H.B.B.-d.-M., P. Boffetta and D.A. contributed with reagents, samples and/or materials and reviewed and approved the final manuscript. J.D.M. and C.I.A. designed and coordinated the Lung Cancer OncoArray. P. Brennan obtained funding for the project and provided overall supervision and management.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Paul Brennan.

Integrated supplementary information

Supplementary information

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  1. 1.

    Supplementary Text and Figures

    Supplementary Figures 1–15 and Supplementary Tables 2, 3 and 12–23.

Excel files

  1. 1.

    Supplementary Table 1

    Description of epidemiological studies in the analysis.

  2. 2.

    Supplementary Table 4

    Overall oral and pharyngeal cancer results (P < 5 × 10–8).

  3. 3.

    Supplementary Table 5

    Oral cancer results (P < 5 × 10–8).

  4. 4.

    Supplementary Table 6

    Oropharynx cancer results (P < 5 × 10–8).

  5. 5.

    Supplementary Table 7

    Overall oral and pharynx cancer results (5 × 10–7 < P > 5 × 10–8).

  6. 6.

    Supplementary Table 8

    Oral cancer results (5 × 10–7 < P > 5 × 10–8).

  7. 7.

    Supplementary Table 9

    Oropharynx cancer results (5 × 10–6 < P >5 × 10–8) in the HLA region.

  8. 8.

    Supplementary Table 10

    Oropharynx cancer results (5 × 10–6 < P > 5 × 10–8), excluding the HLA region.

  9. 9.

    Supplementary Table 11

    Functional annotation of variants at P < 5 × 10–8 in any of the three meta-analyses.

  10. 10.

    Supplementary Table 24

    Conditional analyses for overall oral cavity and pharynx cancer at 6p21.

  11. 11.

    Supplementary Table 25

    Top associations of HLA classical alleles and overall oral and pharynx cancer, OC and OPC risk.

  12. 12.

    Supplementary Table 26

    Overall oral and pharynx cancer associations at 6p21.32 when conditioning on HLA-DRB1*1301–HLA-DQA1*0103–HLA-DQB1*0603 haplotype.

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