Genome-wide association analyses identify new susceptibility loci for oral cavity and pharyngeal cancer (original) (raw)

References

  1. Gillison, M.L., Chaturvedi, A.K., Anderson, W.F. & Fakhry, C. Epidemiology of human papillomavirus–positive head and neck squamous cell carcinoma. J. Clin. Oncol. 33, 3235–3242 (2015).
    Article CAS PubMed PubMed Central Google Scholar
  2. Chaturvedi, A.K. et al. Human papillomavirus and rising oropharyngeal cancer incidence in the United States. J. Clin. Oncol. 29, 4294–4301 (2011).
    Article PubMed PubMed Central Google Scholar
  3. Kreimer, A.R., Clifford, G.M., Boyle, P. & Franceschi, S. Human papillomavirus types in head and neck squamous cell carcinomas worldwide: a systematic review. Cancer Epidemiol. Biomarkers Prev. 14, 467–475 (2005).
    Article CAS PubMed Google Scholar
  4. Ribeiro, K.B. 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).
    Article PubMed Google Scholar
  5. López, R.V. 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).
    Article PubMed Google Scholar
  6. Hashibe, M. et al. Multiple ADH genes are associated with upper aerodigestive cancers. Nat. Genet. 40, 707–709 (2008).
    Article CAS PubMed Google Scholar
  7. McKay, J.D. et al. A genome-wide association study of upper aerodigestive tract cancers conducted within the INHANCE consortium. PLoS Genet. 7, e1001333 (2011).
    Article CAS PubMed PubMed Central Google Scholar
  8. McCarthy, S. et al. A reference panel of 64,976 haplotypes for genotype imputation. Nat. Genet. 48, 1279–1283 (2016).
    Article CAS PubMed PubMed Central Google Scholar
  9. de Bakker, P.I. et al. Practical aspects of imputation-driven meta-analysis of genome-wide association studies. Hum. Mol. Genet. 17 R2, R122–R128 (2008).
    Article CAS PubMed PubMed Central Google Scholar
  10. Hashibe, M. 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).
    Article CAS PubMed Google Scholar
  11. Chang, J.S., Straif, K. & Guha, N. 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).
    Article CAS PubMed Google Scholar
  12. Ramasamy, A. et al. Genetic variability in the regulation of gene expression in ten regions of the human brain. Nat. Neurosci. 17, 1418–1428 (2014).
    Article CAS PubMed PubMed Central Google Scholar
  13. Carré, C. & Shiekhattar, R. Human GTPases associate with RNA polymerase II to mediate its nuclear import. Mol. Cell. Biol. 31, 3953–3962 (2011).
    Article PubMed PubMed Central Google Scholar
  14. GTEx Consortium. The Genotype-Tissue Expression (GTEx) pilot analysis: multitissue gene regulation in humans. Science 348, 648–660 (2015).
  15. McKay, J.D. et al. Lung cancer susceptibility locus at 5p15.33. Nat. Genet. 40, 1404–1406 (2008).
    Article CAS PubMed PubMed Central Google Scholar
  16. Wang, Y. et al. Common 5p15.33 and 6p21.33 variants influence lung cancer risk. Nat. Genet. 40, 1407–1409 (2008).
    CAS PubMed PubMed Central Google Scholar
  17. Rafnar, T. et al. Sequence variants at the TERT_–_CLPTM1L locus associate with many cancer types. Nat. Genet. 41, 221–227 (2009).
    Article CAS PubMed PubMed Central Google Scholar
  18. Stacey, S.N. et al. New common variants affecting susceptibility to basal cell carcinoma. Nat. Genet. 41, 909–914 (2009).
    Article CAS PubMed PubMed Central Google Scholar
  19. Yin, J. et al. TERT_–_CLPTM1L rs401681 C>T polymorphism was associated with a decreased risk of esophageal cancer in a Chinese population. PLoS One 9, e100667 (2014).
    Article PubMed PubMed Central Google Scholar
  20. Petersen, G.M. 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).
    Article CAS PubMed PubMed Central Google Scholar
  21. Bei, J.X. 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).
    Article CAS PubMed Google Scholar
  22. Law, M.H. et al. Genome-wide meta-analysis identifies five new susceptibility loci for cutaneous malignant melanoma. Nat. Genet. 47, 987–995 (2015).
    Article CAS PubMed PubMed Central Google Scholar
  23. Shete, S. et al. Genome-wide association study identifies five susceptibility loci for glioma. Nat. Genet. 41, 899–904 (2009).
    Article CAS PubMed PubMed Central Google Scholar
  24. Turnbull, C. et al. Genome-wide association study identifies five new breast cancer susceptibility loci. Nat. Genet. 42, 504–507 (2010).
    Article CAS PubMed PubMed Central Google Scholar
  25. Timofeeva, M.N. 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).
    Article CAS PubMed PubMed Central Google Scholar
  26. Bei, J.X. et al. A genome-wide association study of nasopharyngeal carcinoma identifies three new susceptibility loci. Nat. Genet. 42, 599–603 (2010).
    Article CAS PubMed Google Scholar
  27. Wu, C. et al. Joint analysis of three genome-wide association studies of esophageal squamous cell carcinoma in Chinese populations. Nat. Genet. 46, 1001–1006 (2014).
    Article CAS PubMed PubMed Central Google Scholar
  28. Cancer Genome Atlas Network. Comprehensive genomic characterization of head and neck squamous cell carcinomas. Nature 517, 576–582 (2015).
  29. Barak, T. et al. Recessive LAMC3 mutations cause malformations of occipital cortical development. Nat. Genet. 43, 590–594 (2011).
    Article CAS PubMed PubMed Central Google Scholar
  30. Chen, D. et al. Genome-wide association study of susceptibility loci for cervical cancer. J. Natl. Cancer Inst. 105, 624–633 (2013).
    Article CAS PubMed Google Scholar
  31. Bouvard, V. et al. A review of human carcinogens—Part B: biological agents. Lancet Oncol. 10, 321–322 (2009).
    Article PubMed Google Scholar
  32. Thibodeau, J., Bourgeois-Daigneault, M.C. & Lapointe, R. Targeting the MHC class II antigen presentation pathway in cancer immunotherapy. OncoImmunology 1, 908–916 (2012).
    Article PubMed PubMed Central Google Scholar
  33. Anonymous. Consortium launches genotyping effort. Cancer Discov. 3, 1321–1322 (2013).
  34. Price, A.L. et al. Principal components analysis corrects for stratification in genome-wide association studies. Nat. Genet. 38, 904–909 (2006).
    Article CAS PubMed Google Scholar
  35. Falush, D., Stephens, M. & Pritchard, J.K. Inference of population structure using multilocus genotype data: linked loci and correlated allele frequencies. Genetics 164, 1567–1587 (2003).
    CAS PubMed PubMed Central Google Scholar
  36. Das, S. et al. Next-generation genotype imputation service and methods. Nat. Genet. 48, 1284–1287 (2016).
    Article CAS PubMed PubMed Central Google Scholar
  37. Delaneau, O., Marchini, J. & Zagury, J.F. A linear complexity phasing method for thousands of genomes. Nat. Methods 9, 179–181 (2011).
    Article PubMed Google Scholar
  38. Fuchsberger, C., Abecasis, G.R. & Hinds, D.A. minimac2: faster genotype imputation. Bioinformatics 31, 782–784 (2015).
    Article CAS PubMed Google Scholar
  39. Purcell, S. et al. PLINK: a tool set for whole-genome association and population-based linkage analyses. Am. J. Hum. Genet. 81, 559–575 (2007).
    Article CAS PubMed PubMed Central Google Scholar
  40. Jia, X. et al. Imputing amino acid polymorphisms in human leukocyte antigens. PLoS One 8, e64683 (2013).
    Article CAS PubMed PubMed Central Google Scholar
  41. Ward, L.D. & Kellis, M. 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).
    Article CAS PubMed Google Scholar
  42. Turner, S.D. qqman: an R package for visualizing GWAS results using Q–Q and Manhattan plots. Preprint at bioRxiv http://dx.doi.org/10.1101/005165 (2014).
  43. Viechtbauer, W. Conducting meta-analyses in R with the metafor package. J. Stat. Softw. 36, 48 (2010).
    Article Google Scholar
  44. Pruim, R.J. et al. LocusZoom: regional visualization of genome-wide association scan results. Bioinformatics 26, 2336–2337 (2010).
    Article CAS PubMed PubMed Central Google Scholar
  45. Machiela, M.J. & Chanock, S.J. LDlink: a web-based application for exploring population-specific haplotype structure and linking correlated alleles of possible functional variants. Bioinformatics 31, 3555–3557 (2015).
    Article CAS PubMed PubMed Central Google Scholar

Download references

Acknowledgements

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

  1. Xavier Castellsagué: Deceased.

Authors and Affiliations

  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

Authors

  1. Corina Lesseur
  2. Brenda Diergaarde
  3. Andrew F Olshan
  4. Victor Wünsch-Filho
  5. Andrew R Ness
  6. Geoffrey Liu
  7. Martin Lacko
  8. José Eluf-Neto
  9. Silvia Franceschi
  10. Pagona Lagiou
  11. Gary J Macfarlane
  12. Lorenzo Richiardi
  13. Stefania Boccia
  14. Jerry Polesel
  15. Kristina Kjaerheim
  16. David Zaridze
  17. Mattias Johansson
  18. Ana M Menezes
  19. Maria Paula Curado
  20. Max Robinson
  21. Wolfgang Ahrens
  22. Cristina Canova
  23. Ariana Znaor
  24. Xavier Castellsagué
  25. David I Conway
  26. Ivana Holcátová
  27. Dana Mates
  28. Marta Vilensky
  29. Claire M Healy
  30. Neonila Szeszenia-Dąbrowska
  31. Eleonóra Fabiánová
  32. Jolanta Lissowska
  33. Jennifer R Grandis
  34. Mark C Weissler
  35. Eloiza H Tajara
  36. Fabio D Nunes
  37. Marcos B de Carvalho
  38. Steve Thomas
  39. Rayjean J Hung
  40. Wilbert H M Peters
  41. Rolando Herrero
  42. Gabriella Cadoni
  43. H Bas Bueno-de-Mesquita
  44. Annika Steffen
  45. Antonio Agudo
  46. Oxana Shangina
  47. Xiangjun Xiao
  48. Valérie Gaborieau
  49. Amélie Chabrier
  50. Devasena Anantharaman
  51. Paolo Boffetta
  52. Christopher I Amos
  53. James D McKay
  54. Paul Brennan

Contributions

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.

Corresponding author

Correspondence toPaul Brennan.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Integrated supplementary information

Supplementary Figure 2 Quantile–quantile plots of GWAS meta-analyses.

Analyses of GWAS by geographic region: Europe, South America and North America (adjusted by age, sex and region eigenvectors). (a–c) Overall oral cavity and pharynx cancer (λ = 1.06) (a), oral cancer (λ = 1.05) (b) and oropharyngeal cancer (λ = 1.04) (c).

Supplementary Figure 3 Quantile–quantile plots of GWAS by region.

Top, overall oral and pharyngeal cancer; middle, oral cancer; bottom, oropharyngeal cancer. Plots for Europe, North America and South America are shown from left to right. All analyses were adjusted by age, sex and eigenvectors.

Supplementary Figure 4 Regional association plot of the oral and pharyngeal cancer analysis at 10q26.13.

Chromosome position (x axis) and –log10 P value (y axis) for oral cavity and pharynx cancer. LD information and recombination rates are from the 1000 Genomes Project November 2014 release (EUR population). Genome coordinates are according to NCBI genome Build 37 (hg19). Genotyped and imputed variants are colored according to their LD with the labeled SNP (purple diamond).

Supplementary Figure 5 Regional association plot of the oral and pharyngeal cancer analysis at 11p15.4.

Chromosome position (x axis) and –log10 P value (y axis) for oral cavity and pharynx cancer. LD information and recombination rates are from the 1000 Genomes Project November 2014 release (EUR population). Genome coordinates are according to NCBI genome Build 37 (hg19). Genotyped and imputed variants are colored according to their LD with the labeled SNP (purple diamond).

Supplementary Figure 6 Regional association plot of the oral cancer analysis at 2p23.3.

Chromosome position (x axis) and –log10 P value (y axis) for oral cancer. LD information and recombination rates are from the 1000 Genomes Project November 2014 release (EUR population). Genome coordinates are according to NCBI genome Build 37 (hg19). Genotyped and imputed variants are colored according to their LD with the labeled SNP (purple diamond).

Supplementary Figure 7 Regional association plot of the oral cancer analysis at 5p15.33.

(a,b) Results for rs10462706 (a) and rs467095 (second strongest association) (b). Chromosome position (x axis) and –log10 P value (y axis) are plotted for oral cancer. LD information and recombination rates are from the 1000 Genomes Project November 2014 release (EUR population). Genome coordinates are according to NCBI genome Build 37 (hg19). Genotyped and imputed variants are colored according to their LD with the labeled SNP (purple diamond).

Supplementary Figure 9 Regional association plot of the oral cancer analysis at 9p21.3.

Chromosome position (x axis) and the –log10 P value (y axis) for oral cancer. LD and recombination rates are from the 1000 Genomes Project November 2014 release (EUR population). Genome coordinates are according to NCBI genome Build 37 (hg19). The plots show genotyped and imputed variants colored according to their LD with the labeled SNP (purple diamond).

Supplementary Figure 10 Regional association plot of the oral cancer analysis at 9q34.

Chromosome position (x axis) and –log10 P value (y axis) for oral cancer. LD and recombination rates are from the 1000 Genomes Project November 2014 release (EUR population). Genome coordinates are according to NCBI genome Build 37 (hg19). The plots show genotyped and imputed variants colored according to their LD with the labeled SNP (purple diamond).

Supplementary Figure 11 Regional association plot of the oral and pharyngeal cancer analysis at 6p21.3.

Chromosome position (x axis) and –log10 P value (y axis) for oral cancer. LD and recombination rates are from the 1000 Genomes Project November 2014 release (EUR population). Genome coordinates are according to NCBI genome Build 37 (hg19). The plots show genotyped and imputed variants colored according to their LD with the labeled SNP (purple diamond).

Supplementary Figure 12 Genotype cluster plots of top loci.

(a–h) Plots are shown for 2p23 rs1919126 (a), 9p21.3 rs8181047 (b), 6p21.32 rs3134995 (c), 5p15.3 rs467095 (d), 9q34 rs199717881/chr9_133953882_A_C (e), 10q26 rs201982221/chr10_126157446_CAG_INDEL (f), 11p15 rs1453414/chr11_5829084_G_T (g) and 5p14 rs79767424/chr5_19108690_G_T (SNP not validated by TaqMan) (h).

Supplementary Figure 13 Principal-components analyses plots.

(a–d) Plots are shown for all study participants (a) and for those within the regions of Europe (b), North America (c) and South America (d). Principal component 1 is displayed on the x axis, and principal component 2 is displayed on the y axis. Blue dots are cases, and black dots are controls.

Supplementary Figure 14 Principal-components analyses by epidemiological study.

Principal component 1 is displayed on the x axis, and principal component 2 is displayed on the y axis. Blue dots are cases, and black dots are controls.

Supplementary Figure 15 Sequence chromatogram of rs201982221 (10q26.13).

(a) Example of wild-type insertion. (b) Example of homozygous deletion. The deletion start corresponds to nucleotide 105 in the chromatogram.

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Lesseur, C., Diergaarde, B., Olshan, A. et al. Genome-wide association analyses identify new susceptibility loci for oral cavity and pharyngeal cancer.Nat Genet 48, 1544–1550 (2016). https://doi.org/10.1038/ng.3685

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