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A genome-wide association study of nasopharyngeal carcinoma identifies three new susceptibility loci

Nature Genetics volume 42, pages 599–603 (2010)Cite this article

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Abstract

To identify genetic susceptibility loci for nasopharyngeal carcinoma (NPC), a genome-wide association study was performed using 464,328 autosomal SNPs in 1,583 NPC affected individuals (cases) and 1,894 controls of southern Chinese descent. The top 49 SNPs from the genome-wide association study were genotyped in 3,507 cases and 3,063 controls of southern Chinese descent from Guangdong and Guangxi. The seven supportive SNPs were further confirmed by transmission disequilibrium test analysis in 279 trios from Guangdong. We identified three new susceptibility loci, TNFRSF19 on 13q12 (rs9510787, Pcombined = 1.53 × 10−9, odds ratio (OR) = 1.20), MDS1-EVI1 on 3q26 (rs6774494, Pcombined = 1.34 × 10−8, OR = 0.84) and the CDKN2A-CDKN2B gene cluster on 9p21 (rs1412829, Pcombined = 4.84 × 10−7, OR = 0.78). Furthermore, we confirmed the role of HLA by revealing independent associations at rs2860580 (Pcombined = 4.88 × 10−67, OR = 0.58), rs2894207 (Pcombined = 3.42 × 10−33, OR = 0.61) and rs28421666 (Pcombined = 2.49 × 10−18, OR = 0.67). Our findings provide new insights into the pathogenesis of NPC by highlighting the involvement of pathways related to TNFRSF19 and MDS1-EVI1 in addition to HLA molecules.

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Figure 1: Manhattan plot of the genome-wide P values of association.
Figure 2: Regional plots of association results and recombination rates within three non-HLA susceptibility loci.

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References

  1. Wei, W.I. & Sham, J.S. Nasopharyngeal carcinoma. Lancet 365, 2041–2054 (2005).

    Article  Google Scholar 

  2. McDermott, A.L., Dutt, S.N. & Watkinson, J.C. The aetiology of nasopharyngeal carcinoma. Clin. Otolaryngol. Allied Sci. 26, 82–92 (2001).

    Article  CAS  Google Scholar 

  3. Yu, M.C. & Yuan, J.M. Epidemiology of nasopharyngeal carcinoma. Semin. Cancer Biol. 12, 421–429 (2002).

    Article  Google Scholar 

  4. Zeng, Y.X. & Jia, W.H. Familial nasopharyngeal carcinoma. Semin. Cancer Biol. 12, 443–450 (2002).

    Article  CAS  Google Scholar 

  5. Li, D.J. et al. The dominance of China 1 in the spectrum of Epstein-Barr virus strains from Cantonese patients with nasopharyngeal carcinoma. J. Med. Virol. 81, 1253–1260 (2009).

    Article  CAS  Google Scholar 

  6. Young, L.S. & Rickinson, A.B. Epstein-Barr virus: 40 years on. Nat. Rev. Cancer 4, 757–768 (2004).

    Article  CAS  Google Scholar 

  7. Lu, S.J. et al. Linkage of a nasopharyngeal carcinoma susceptibility locus to the HLA region. Nature 346, 470–471 (1990).

    Article  CAS  Google Scholar 

  8. Lu, C.C. et al. Nasopharyngeal carcinoma-susceptibility locus is localized to a 132 kb segment containing HLA-A using high-resolution microsatellite mapping. Int. J. Cancer 115, 742–746 (2005).

    Article  CAS  Google Scholar 

  9. Feng, B.J. et al. Genome-wide scan for familial nasopharyngeal carcinoma reveals evidence of linkage to chromosome 4. Nat. Genet. 31, 395–399 (2002).

    Article  CAS  Google Scholar 

  10. Xiong, W. et al. A susceptibility locus at chromosome 3p21 linked to familial nasopharyngeal carcinoma. Cancer Res. 64, 1972–1974 (2004).

    Article  CAS  Google Scholar 

  11. Hu, L.F. et al. A genome-wide scan suggests a susceptibility locus on 5p 13 for nasopharyngeal carcinoma. Eur. J. Hum. Genet. 16, 343–349 (2008).

    Article  CAS  Google Scholar 

  12. Tse, K.P. et al. Genome-wide association study reveals multiple nasopharyngeal carcinoma-associated loci within the HLA region at chromosome 6p21.3. Am. J. Hum. Genet. 85, 194–203 (2009).

    Article  CAS  Google Scholar 

  13. Ng, C.C. et al. A genome-wide association study identifies ITGA9 conferring risk of nasopharyngeal carcinoma. J. Hum. Genet. 54, 392–397 (2009).

    Article  CAS  Google Scholar 

  14. Chen, J. et al. Genetic structure of the Han Chinese population revealed by genome-wide SNP variation. Am. J. Hum. Genet. 85, 775–785 (2009).

    Article  CAS  Google Scholar 

  15. Hildesheim, A. et al. Association of HLA class I and II alleles and extended haplotypes with nasopharyngeal carcinoma in Taiwan. J. Natl. Cancer Inst. 94, 1780–1789 (2002).

    Article  CAS  Google Scholar 

  16. Skibola, C.F. et al. Genetic variants at 6p21.33 are associated with susceptibility to follicular lymphoma. Nat. Genet. 41, 873–875 (2009).

    Article  CAS  Google Scholar 

  17. Rickinson, A.B. & Moss, D.J. Human cytotoxic T lymphocyte responses to Epstein-Barr virus infection. Annu. Rev. Immunol. 15, 405–431 (1997).

    Article  CAS  Google Scholar 

  18. Hu, S., Tamada, K., Ni, J., Vincenz, C. & Chen, L. Characterization of TNFRSF19, a novel member of the tumor necrosis factor receptor superfamily. Genomics 62, 103–107 (1999).

    Article  CAS  Google Scholar 

  19. Eby, M.T., Jasmin, A., Kumar, A., Sharma, K. & Chaudhary, P.M. TAJ, a novel member of the tumor necrosis factor receptor family, activates the c-Jun N-terminal kinase pathway and mediates caspase-independent cell death. J. Biol. Chem. 275, 15336–15342 (2000).

    Article  CAS  Google Scholar 

  20. Morikawa, Y., Hisaoka, T., Kitamura, T. & Senba, E. TROY, a novel member of the tumor necrosis factor receptor superfamily in the central nervous system. Ann. NY Acad. Sci. 1126, A1–A10 (2008).

    Article  Google Scholar 

  21. Eliopoulos, A.G. & Young, L.S. LMP1 structure and signal transduction. Semin. Cancer Biol. 11, 435–444 (2001).

    Article  CAS  Google Scholar 

  22. Métais, J.Y. & Dunbar, C.E. The MDS1–EVI1 gene complex as a retrovirus integration site: impact on behavior of hematopoietic cells and implications for gene therapy. Mol. Ther. 16, 439–449 (2008).

    Article  Google Scholar 

  23. Kurokawa, M. et al. The evi-1 oncoprotein inhibits c-Jun N-terminal kinase and prevents stress-induced cell death. EMBO J. 19, 2958–2968 (2000).

    Article  CAS  Google Scholar 

  24. Nitta, E. et al. Oligomerization of Evi-1 regulated by the PR domain contributes to recruitment of corepressor CtBP. Oncogene 24, 6165–6173 (2005).

    Article  CAS  Google Scholar 

  25. Xu, J., Menezes, J., Prasad, U. & Ahmad, A. Elevated serum levels of transforming growth factor beta1 in Epstein-Barr virus-associated nasopharyngeal carcinoma patients. Int. J. Cancer 84, 396–399 (1999).

    Article  CAS  Google Scholar 

  26. Chou, J. et al. Nasopharyngeal carcinoma–review of the molecular mechanisms of tumorigenesis. Head Neck 30, 946–963 (2008).

    Article  Google Scholar 

  27. Sharpless, N.E. et al. Loss of p16Ink4a with retention of p19Arf predisposes mice to tumorigenesis. Nature 413, 86–91 (2001).

    Article  CAS  Google Scholar 

  28. Krimpenfort, P. et al. p15Ink4b is a critical tumour suppressor in the absence of p16Ink4a. Nature 448, 943–946 (2007).

    Article  CAS  Google Scholar 

  29. Lo, K.W. & Huang, D.P. Genetic and epigenetic changes in nasopharyngeal carcinoma. Semin. Cancer Biol. 12, 451–462 (2002).

    Article  CAS  Google Scholar 

  30. Wrensch, M. et al. Variants in the CDKN2B and RTEL1 regions are associated with high-grade glioma susceptibility. Nat. Genet. 41, 905–908 (2009).

    Article  CAS  Google Scholar 

  31. Chen, M.C. et al. The incidence and risk of second primary cancers in patients with nasopharyngeal carcinoma: a population-based study in Taiwan over a 25-year period (1979–2003). Ann. Oncol. 19, 1180–1186 (2008).

    Article  Google Scholar 

  32. Scélo, G. et al. Second primary cancers in patients with nasopharyngeal carcinoma: a pooled analysis of 13 cancer registries. Cancer Causes Control 18, 269–278 (2007).

    Article  Google Scholar 

  33. 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  Google Scholar 

  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  Google Scholar 

  35. Barrett, J.C., Fry, B., Maller, J. & Daly, M.J. Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics 21, 263–265 (2005).

    Article  CAS  Google Scholar 

  36. Xu, S. et al. Genomic dissection of population substructure of Han Chinese and its implication in association studies. Am. J. Hum. Genet. 85, 762–774 (2009).

    Article  CAS  Google Scholar 

  37. Kazeem, G.R. & Farrall, M. Integrating case-control and TDT studies. Ann. Hum. Genet. 69, 329–335 (2005).

    Article  CAS  Google Scholar 

  38. Agresti, A. Categorical Data Analysis (John Wiley and Sons, New York, 1990).

  39. Stephens, M., Smith, N.J. & Donnelly, P. A new statistical method for haplotype reconstruction from population data. Am. J. Hum. Genet. 68, 978–989 (2001).

    Article  CAS  Google Scholar 

  40. de Bakker, P.I. et al. A high-resolution HLA and SNP haplotype map for disease association studies in the extended human MHC. Nat. Genet. 38, 1166–1172 (2006).

    Article  CAS  Google Scholar 

  41. Feng, B.J. et al. Multiple loci within the major histocompatibility complex confer risk of psoriasis. PLoS Genet. 5, e1000606 (2009).

    Article  Google Scholar 

  42. Stephens, M. & Scheet, P. Accounting for decay of linkage disequilibrium in haplotype inference and missing-data imputation. Am. J. Hum. Genet. 76, 449–462 (2005).

    Article  CAS  Google Scholar 

  43. Mensah, F.K. et al. Haplotype uncertainty in association studies. Genet. Epidemiol. 31, 348–357 (2007).

    Article  CAS  Google Scholar 

  44. Marchini, J., Howie, B., Myers, S., McVean, G. & Donnelly, P. A new multipoint method for genome-wide association studies by imputation of genotypes. Nat. Genet. 39, 906–913 (2007).

    Article  CAS  Google Scholar 

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Acknowledgements

We would like to thank all the subjects and healthy volunteers who participated in this work. We also want to thank the staffs of Bank of Tumor Resource at Sun Yat-sen University Cancer Center (SYSUCC) for help in sample storage. We also want to thank W.-Y. Meah, X. Chen, H.-B. Toh, K.-K. Heng, C.-H. Wong and D.E.K. Tan, who performed the genotyping, and R.T.H. Ong, J. Chen, K.-S. Sim and E. Tantoso for their assistance in data analysis. This work was funded by the High-Tech Research and Development Program of China (863 Plan, 2006AA02A404), the Natural Science Foundation of China (30621063, 30872929 and u0732005), the National Basic Research Program of China (973 Plan; 2004CB518604 and 2006CB910104), Beijing Science & Technology nova program (2006A54), the National Science and Technology Support Program of China (2006BAI02A11) and the Agency for Science, Technology and Research of Singapore.

Author information

Author notes

  1. Jin-Xin Bei and Yi Li: These authors contributed equally to the work.

  2. Jianjun Liu and Yi-Xin Zeng: These authors jointly directed this work.

Authors and Affiliations

  1. State Key Laboratory of Oncology in Southern China, Guangzhou, China

    Jin-Xin Bei, Wei-Hua Jia, Bing-Jian Feng, Li-Zhen Chen, Qi-Sheng Feng, Tiebang Kang, Jianjun Liu & Yi-Xin Zeng

  2. Department of Experimental Research, Sun Yat-sen University Cancer Center, Guangzhou, China

    Jin-Xin Bei, Wei-Hua Jia, Bing-Jian Feng, Li-Zhen Chen, Qi-Sheng Feng, Tiebang Kang & Yi-Xin Zeng

  3. Human Genetics, Genome Institute of Singapore, A*STAR, Singapore

    Yi Li, Hui-Qi Low & Jianjun Liu

  4. Department of Dermatology, University of Utah School of Medicine, Salt Lake City, Utah, USA

    Bing-Jian Feng

  5. The State Key Laboratory of Proteomics, Beijing Proteome Research Center, Beijing Institute of Radiation Medicine, Beijing, China

    Gangqiao Zhou, Hongxing Zhang & Fuchu He

  6. Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore

    E Shyong Tai

  7. Department of Epidemiology and Public Health, Yong Loo Lin School of Medicine, National University of Singapore, Singapore

    E Shyong Tai

  8. Cancer Biology, Genome Institute of Singapore, A*STAR, Singapore

    Edison T Liu

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Contributions

Y.-X.Z. was the overall study principal investigator who conceived the study and obtained financial support. Y.-X.Z., J.-X.B. and J.L. designed and oversaw the study. W.-H.J., B.-J.F., Q.-S.F. and L.-Z.C. initiated or participated in the recruitment of Guangdong Chinese samples and preparation of biological samples. H.Z., G.Z. and F.H. were responsible for the recruitment and sample preparation of Guangxi Chinese samples. J.-X.B. conducted sample inclusion and data management. B.-J.F. helped to impute the HLA alleles. J.-X.B. and Y.L. undertook the statistical analyses under guidance from J.L. and with help from H.-Q.L. J.-X.B. interpreted the results, drafted and synthesized the manuscript. E.T.L., T.K. and E.S.T. reviewed the manuscript and J.L. helped to revise it.

Corresponding authors

Correspondence to Jianjun Liu or Yi-Xin Zeng.

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The authors declare no competing financial interests.

Supplementary information

Supplementary Text and Figures

Supplementary Note, Supplementary Tables 1–17 and Supplementary Figures 1–5 (PDF 2569 kb)

Supplementary Table 1

Summary of previous studies on the associations of HLA genes and nasopharyngeal carcinoma. (XLS 32 kb)

Supplementary Table 2

Summary of previous studies on the associations of non-MHC genes and nasopharyngeal carcinoma, based on candidate-gene approach. (XLS 34 kb)

Supplementary Table 3

Our GWAS results of the SNPs that were reported by the previously studies. (XLS 28 kb)

Supplementary Table 5

Association results of the 42 SNPs subjected to the validation analysis. (XLS 30 kb)

Supplementary Table 15

Susceptibility loci of different malignancies identified by GWAS up to March 9, 2010. (XLS 158 kb)

Supplementary References (XLS 48 kb)

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Bei, JX., Li, Y., Jia, WH. et al. A genome-wide association study of nasopharyngeal carcinoma identifies three new susceptibility loci. Nat Genet 42, 599–603 (2010). https://doi.org/10.1038/ng.601

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