Abstract
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, OR52N2–TRIM5). 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.
This is a preview of subscription content, access via your institution
Relevant articles
Open Access articles citing this article.
-
Reviewing the epidemiology of head and neck cancer: definitions, trends and risk factors
British Dental Journal Open Access 11 November 2022
-
Genome-wide analyses of 200,453 individuals yield new insights into the causes and consequences of clonal hematopoiesis
Nature Genetics Open Access 14 July 2022
-
Association between circulating vitamin E and ten common cancers: evidence from large-scale Mendelian randomization analysis and a longitudinal cohort study
BMC Medicine Open Access 11 May 2022
Access options
Subscribe to this journal
Receive 12 print issues and online access
$189.00 per year
only $15.75 per issue
Rent or buy this article
Get just this article for as long as you need it
$39.95
Prices may be subject to local taxes which are calculated during checkout
References
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).
Chaturvedi, A.K. et al. Human papillomavirus and rising oropharyngeal cancer incidence in the United States. J. Clin. Oncol. 29, 4294–4301 (2011).
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).
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).
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).
Hashibe, M. et al. Multiple ADH genes are associated with upper aerodigestive cancers. Nat. Genet. 40, 707–709 (2008).
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).
McCarthy, S. et al. A reference panel of 64,976 haplotypes for genotype imputation. Nat. Genet. 48, 1279–1283 (2016).
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).
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).
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).
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).
Carré, C. & Shiekhattar, R. Human GTPases associate with RNA polymerase II to mediate its nuclear import. Mol. Cell. Biol. 31, 3953–3962 (2011).
GTEx Consortium. The Genotype-Tissue Expression (GTEx) pilot analysis: multitissue gene regulation in humans. Science 348, 648–660 (2015).
McKay, J.D. et al. Lung cancer susceptibility locus at 5p15.33. Nat. Genet. 40, 1404–1406 (2008).
Wang, Y. et al. Common 5p15.33 and 6p21.33 variants influence lung cancer risk. Nat. Genet. 40, 1407–1409 (2008).
Rafnar, T. et al. Sequence variants at the TERT–CLPTM1L locus associate with many cancer types. Nat. Genet. 41, 221–227 (2009).
Stacey, S.N. et al. New common variants affecting susceptibility to basal cell carcinoma. Nat. Genet. 41, 909–914 (2009).
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).
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).
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).
Law, M.H. et al. Genome-wide meta-analysis identifies five new susceptibility loci for cutaneous malignant melanoma. Nat. Genet. 47, 987–995 (2015).
Shete, S. et al. Genome-wide association study identifies five susceptibility loci for glioma. Nat. Genet. 41, 899–904 (2009).
Turnbull, C. et al. Genome-wide association study identifies five new breast cancer susceptibility loci. Nat. Genet. 42, 504–507 (2010).
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).
Bei, J.X. et al. A genome-wide association study of nasopharyngeal carcinoma identifies three new susceptibility loci. Nat. Genet. 42, 599–603 (2010).
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).
Cancer Genome Atlas Network. Comprehensive genomic characterization of head and neck squamous cell carcinomas. Nature 517, 576–582 (2015).
Barak, T. et al. Recessive LAMC3 mutations cause malformations of occipital cortical development. Nat. Genet. 43, 590–594 (2011).
Chen, D. et al. Genome-wide association study of susceptibility loci for cervical cancer. J. Natl. Cancer Inst. 105, 624–633 (2013).
Bouvard, V. et al. A review of human carcinogens—Part B: biological agents. Lancet Oncol. 10, 321–322 (2009).
Thibodeau, J., Bourgeois-Daigneault, M.C. & Lapointe, R. Targeting the MHC class II antigen presentation pathway in cancer immunotherapy. OncoImmunology 1, 908–916 (2012).
Anonymous. Consortium launches genotyping effort. Cancer Discov. 3, 1321–1322 (2013).
Price, A.L. et al. Principal components analysis corrects for stratification in genome-wide association studies. Nat. Genet. 38, 904–909 (2006).
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).
Das, S. et al. Next-generation genotype imputation service and methods. Nat. Genet. 48, 1284–1287 (2016).
Delaneau, O., Marchini, J. & Zagury, J.F. A linear complexity phasing method for thousands of genomes. Nat. Methods 9, 179–181 (2011).
Fuchsberger, C., Abecasis, G.R. & Hinds, D.A. minimac2: faster genotype imputation. Bioinformatics 31, 782–784 (2015).
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).
Jia, X. et al. Imputing amino acid polymorphisms in human leukocyte antigens. PLoS One 8, e64683 (2013).
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).
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).
Viechtbauer, W. Conducting meta-analyses in R with the metafor package. J. Stat. Softw. 36, 48 (2010).
Pruim, R.J. et al. LocusZoom: regional visualization of genome-wide association scan results. Bioinformatics 26, 2336–2337 (2010).
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).
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
Authors and Affiliations
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
Ethics declarations
Competing interests
The authors declare no competing financial interests.
Integrated supplementary information
Supplementary Figure 1 Histograms of imputation quality measure (R2).
(a) Variants with MAF ≥ 0.05. (b) Variants with MAF <0.05.
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 8 Forest plot of odds ratios for oral cancer analysis at rs467095.
EAF, effect allele frequency in 6,585 controls.
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.
Supplementary information
Supplementary Text and Figures
Supplementary Figures 1–15 and Supplementary Tables 2, 3 and 12–23. (PDF 2390 kb)
Supplementary Table 1
Description of epidemiological studies in the analysis. (XLSX 13 kb)
Supplementary Table 4
Overall oral and pharyngeal cancer results (P < 5 × 10–8). (XLSX 34 kb)
Supplementary Table 5
Oral cancer results (P < 5 × 10–8). (XLSX 16 kb)
Supplementary Table 6
Oropharynx cancer results (P < 5 × 10–8). (XLSX 23 kb)
Supplementary Table 7
Overall oral and pharynx cancer results (5 × 10–7 < P > 5 × 10–8). (XLSX 30 kb)
Supplementary Table 8
Oral cancer results (5 × 10–7 < P > 5 × 10–8). (XLSX 26 kb)
Supplementary Table 9
Oropharynx cancer results (5 × 10–6 < P >5 × 10–8) in the HLA region. (XLSX 54 kb)
Supplementary Table 10
Oropharynx cancer results (5 × 10–6 < P > 5 × 10–8), excluding the HLA region. (XLSX 19 kb)
Supplementary Table 11
Functional annotation of variants at P < 5 × 10–8 in any of the three meta-analyses. (XLSX 28 kb)
Supplementary Table 24
Conditional analyses for overall oral cavity and pharynx cancer at 6p21. (XLSX 19 kb)
Supplementary Table 25
Top associations of HLA classical alleles and overall oral and pharynx cancer, OC and OPC risk. (XLSX 14 kb)
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. (XLSX 24 kb)
Source data
Rights and permissions
About this article
Cite this article
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
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/ng.3685
This article is cited by
-
Association between circulating vitamin E and ten common cancers: evidence from large-scale Mendelian randomization analysis and a longitudinal cohort study
BMC Medicine (2022)
-
Genome-wide analyses of 200,453 individuals yield new insights into the causes and consequences of clonal hematopoiesis
Nature Genetics (2022)
-
Genetic susceptibility to patient-reported xerostomia among long-term oropharyngeal cancer survivors
Scientific Reports (2022)
-
Reviewing the epidemiology of head and neck cancer: definitions, trends and risk factors
British Dental Journal (2022)
-
Tumor suppressor LHPP suppresses cell proliferation and epithelial-mesenchymal transition in hepatocellular carcinoma cell lines
Journal of Physiology and Biochemistry (2022)
