Abstract
Prostate cancer is the most prevalent noncutaneous cancer in males in developed regions1, with African American men having among the highest worldwide incidence and mortality rates2. Here we report a second genetic variant in the 8q24 region that, in conjunction with another variant we recently discovered3, accounts for about 11%–13% of prostate cancer cases in individuals of European descent and 31% of cases in African Americans. We made the current discovery through a genome-wide association scan of 1,453 affected Icelandic individuals and 3,064 controls using the Illumina HumanHap300 BeadChip followed by four replication studies. A key step in the discovery was the construction of a 14-SNP haplotype that efficiently tags a relatively uncommon (2%–4%) susceptibility variant in individuals of European descent that happens to be very common (∼42%) in African Americans. The newly identified variant shows a stronger association with affected individuals who have an earlier age at diagnosis.
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References
Parkin, D.M., Bray, F., Ferlay, J. & Pisani, P. Global cancer statistics, 2002. CA Cancer J. Clin. 55, 74–108 (2005).
SEER Cancer Statistics Review, 1975–2003 (eds. Rees, L.A.G. et al.) (National Cancer Institute, Bethesda, Maryland, 2006).
Amundadottir, L.T. et al. A common variant associated with prostate cancer in European and African populations. Nat. Genet. 38, 652–658 (2006).
Freedman, M.L. et al. Admixture mapping identifies 8q24 as a prostate cancer risk locus in African-American men. Proc. Natl. Acad. Sci. USA 103, 14068–14073 (2006).
Lichtenstein, P. et al. Environmental and heritable factors in the causation of cancer–analyses of cohorts of twins from Sweden, Denmark and Finland. N. Engl. J. Med. 343, 78–85 (2000).
Pe'er, I. et al. Evaluating and improving power in whole-genome association studies using fixed marker sets. Nat. Genet. 38, 663–667 (2006).
McVean, G.A. et al. The fine-scale structure of recombination rate variation in the human genome. Science 304, 581–584 (2004).
Mantel, N. & Haenszel, W. Statistical aspects of the analysis of data from retrospective studies of disease. J. Natl. Cancer Inst. 22, 719–748 (1959).
Lohmueller, K.E., Pearce, C.L., Pike, M., Lander, E.S. & Hirschhorn, J.N. Meta-analysis of genetic association studies supports a contribution of common variants to susceptibility to common disease. Nat. Genet. 33, 177–182 (2003).
Trikalinos, T.A., Ntzani, E.E., Contopoulos-Ioannidis, D.G. & Ioannidis, J.P. Establishment of genetic associations for complex diseases is independent of early study findings. Eur. J. Hum. Genet. 12, 762–769 (2004).
Ferber, M.J. et al. Preferential integration of human papillomavirus type 18 near the c-myc locus in cervical carcinoma. Oncogene 22, 7233–7242 (2003).
Ferber, M.J. et al. Positioning of cervical carcinoma and Burkitt lymphoma translocation breakpoints with respect to the human papillomavirus integration cluster in FRA8C at 8q24.13. Cancer Genet. Cytogenet. 154, 1–9 (2004).
Taylor, M.L., Mainous, A.G. III & Wells, B.J. Prostate cancer and sexually transmitted diseases: a meta-analysis. Fam. Med. 37, 506–512 (2005).
Baudis, M. & Cleary, M.L. Progenetix.net: an online repository for molecular cytogenetic aberration data. Bioinformatics 17, 1228–1229 (2001).
Gulcher, J.R., Kristjansson, K., Gudbjartsson, H. & Stefansson, K. Protection of privacy by third-party encryption in genetic research in Iceland. Eur. J. Hum. Genet. 8, 739–742 (2000).
Winckler, W. et al. Comparison of fine-scale recombination rates in humans and chimpanzees. Science 308, 107–111 (2005).
Barrett, J.C. & Cardon, L.R. Evaluating coverage of genome-wide association studies. Nat. Genet. 38, 659–662 (2006).
Gretarsdottir, S. et al. The gene encoding phosphodiesterase 4D confers risk of ischemic stroke. Nat. Genet. 35, 131–138 (2003).
Falk, C.T. & Rubinstein, P. Haplotype relative risks: an easy reliable way to construct a proper control sample for risk calculations. Ann. Hum. Genet. 51, 227–233 (1987).
Grant, S.F. et al. Variant of transcription factor 7-like 2 (TCF7L2) gene confers risk of type 2 diabetes. Nat. Genet. 38, 320–323 (2006).
Devlin, B. & Roeder, K. Genomic control for association studies. Biometrics 55, 997–1004 (1999).
Devlin, B., Bacanu, S-A. & Roeder, K. Genomic control to the extreme. Nat. Genet. 36, 1129–1130 (2004).
Acknowledgements
We thank the patients and their family members whose contributions made this work possible. We also thank the nurses at Noatun (deCODE's sample recruitment center), personnel at the deCODE core facilities and at the Department of Pathology at Landspitali University Hospital for their hard work and enthusiasm. We acknowledge M. Gielzak, G. Yan and J. Sauvageot (Johns Hopkins Hospital) for their assistance and W.T. Gerrard, M. Duhon, John and Jennifer Chalsty and D. Koch (also at Johns Hopkins Hospital) for their support. We also thank participants and clinicians at the Northwestern University, the University of Chicago, Johns Hopkins Hospital, the Radboud University Nijmegen Medical Centre and the Oncology Department of the Zaragoza Hospital. This project was funded in part by contract number 018827 (Polygene) from the 6th Framework Program of the European Union and by Department of Defense Congressionally Directed Medical Research Program grant W81XWH-05-1-0074.
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The principal investigators of the replication sample sets are J.I.M., L.A.K., W.B.I. and W.J.C.
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J.G., P.S., A.M., L.T.A., D.G., A.H., T.R., J.T.B., A.B., A.S., M.J., T.B., J.K., S.G., S.N.S., M.M., J. Saemundsdottir, V.M.B., K.K., M.F., J.R.G., U.T., A.K. and K.S. are employees of and shareholders in deCODE genetics.
Supplementary information
Supplementary Fig. 1
Estimates of relative risk for haplotypes defined by rs16901979 and rs1447295. (PDF 17 kb)
Supplementary Fig. 2
A Q-Q plot of the 316,515 chi-square statistics from the single point association. (PDF 46 kb)
Supplementary Table 1
Block-haplotypes with estimated frequency 1% or higher in the two LD blocks containing rs1447295 and HapC/rs16901979. (PDF 29 kb)
Supplementary Table 2
Age at diagnosis for prostate cancer in Iceland, Spain, the Netherlands and the US. (PDF 15 kb)
Supplementary Table 3
Distribution of observed and expected association results, by chromosome and significance level, for the 316,515 SNPs used in the genome-wide association analysis of the Icelandic prostate cancer cases and controls. (PDF 17 kb)
Supplementary Table 4
Information about primers and assays. (PDF 20 kb)
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Gudmundsson, J., Sulem, P., Manolescu, A. et al. Genome-wide association study identifies a second prostate cancer susceptibility variant at 8q24. Nat Genet 39, 631–637 (2007). https://doi.org/10.1038/ng1999
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DOI: https://doi.org/10.1038/ng1999
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