Recently, common variants on human chromosome 8q24 were found to be associated with prostate cancer risk. While conducting a genome-wide association study in the Cancer Genetic Markers of Susceptibility project with 550,000 SNPs in a nested case-control study (1,172 cases and 1,157 controls of European origin), we identified a new association at 8q24 with an independent effect on prostate cancer susceptibility. The most significant signal is 70 kb centromeric to the previously reported SNP, rs1447295, but shows little evidence of linkage disequilibrium with it. A combined analysis with four additional studies (total: 4,296 cases and 4,299 controls) confirms association with prostate cancer for rs6983267 in the centromeric locus (P = 9.42 × 10−13; heterozygote odds ratio (OR): 1.26, 95% confidence interval (c.i.): 1.13–1.41; homozygote OR: 1.58, 95% c.i.: 1.40–1.78). Each SNP remained significant in a joint analysis after adjusting for the other (rs1447295 P = 1.41 × 10−11; rs6983267 P = 6.62 × 10−10). These observations, combined with compelling evidence for a recombination hotspot between the two markers, indicate the presence of at least two independent loci within 8q24 that contribute to prostate cancer in men of European ancestry. We estimate that the population attributable risk of the new locus, marked by rs6983267, is higher than the locus marked by rs1447295 (21% versus 9%).
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Crawford, E.D. Epidemiology of prostate cancer. Urology 62, 3–12 (2003).
Parkin, D.M. et al. Cancer Incidence in Five Continents (IARC Scientific Publications, Lyon, 2002).
Steinberg, G.D., Carter, B.S., Beaty, T.H., Childs, B. & Walsh, P.C. Family history and the risk of prostate cancer. Prostate 17, 337–347 (1990).
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).
Amundadottir, L.T. et al. A common variant associated with prostate cancer in European and African populations. Nat. Genet. 38, 652–658 (2006).
Schumacher, F.R. et al. Prostate cancer risk and 8q24. Cancer Res. (in the press).
Gohagan, J.K., Prorok, P.C., Hayes, R.B. & Kramer, B.S. The Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial of the National Cancer Institute: history, organization, and status. Control. Clin. Trials 21, 251S–272S (2000).
Prorok, P.C. et al. Design of the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial. Control. Clin. Trials 21, 273S–309S (2000).
Phillips, M.S. et al. Chromosome-wide distribution of haplotype blocks and the role of recombination hot spots. Nat. Genet. 33, 382–387 (2003).
Calle, E.E. et al. The American Cancer Society Cancer Prevention Study II Nutrition Cohort: rationale, study design, and baseline characteristics. Cancer 94, 2490–2501 (2002).
Chen, Y.C. et al. Sequence variants of Toll-like receptor 4 and susceptibility to prostate cancer. Cancer Res. 65, 11771–11778 (2005).
Valeri, A. et al. Segregation analysis of prostate cancer in France: evidence for autosomal dominant inheritance and residual brother-brother dependence. Ann. Hum. Genet. 67, 125–137 (2003).
The ATBC Cancer Prevention Study Group. The alpha-tocopherol, beta-carotene lung cancer prevention study: design, methods, participant characteristics and compliance. Ann. Epidemiol. 4, 1–10 (1994).
Fearnhead, P. SequenceLDhot: detecting recombination hotspots. Bioinformatics 22, 3061–3066 (2006).
Myers, S., Bottolo, L., Freeman, C., McVean, G. & Donnelly, P. A fine-scale map of recombination rates and hotspots across the human genome. Science 310, 321–324 (2005).
The International HapMap Consortium. A haplotype map of the human genome. Nature 437, 1299–1320 (2005).
Minichiello, M.J. & Durbin, R. Mapping trait loci by use of inferred ancestral recombination graphs. Am. J. Hum. Genet. 79, 910–922 (2006).
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).
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).
Nupponen, N.N., Kakkola, L., Koivisto, P. & Visakorpi, T. Genetic alterations in hormone-refractory recurrent prostate carcinomas. Am. J. Pathol. 153, 141–148 (1998).
Cher, M.L. et al. Genetic alterations in untreated metastases and androgen-independent prostate cancer detected by comparative genomic hybridization and allelotyping. Cancer Res. 56, 3091–3102 (1996).
Bruzzi, P., Green, S.B., Byar, D.P., Brinton, L.A. & Schairer, C. Estimating the population attributable risk for multiple risk factors using case-control data. Am. J. Epidemiol. 122, 904–914 (1985).
Wacholder, S., Benichou, J., Heineman, E.F., Hartge, P. & Hoover, R.N. Attributable risk: advantages of a broad definition of exposure. Am. J. Epidemiol. 140, 303–309 (1994).
Seldin, M.F. et al. European population substructure: clustering of northern and southern populations. PLoS Genet. 2, e143 (2006).
Saarela, J. et al. PRKCA and multiple sclerosis: association in two independent populations. PLoS Genet. 2, e42 (2006).
Willer, C.J. et al. Tag SNP selection for Finnish individuals based on the CEPH Utah HapMap database. Genet. Epidemiol. 30, 180–190 (2006).
The HPFS study is supported by NIH grants CA CA55075 and 5U01CA098233-04. The ACS study is supported by U01 CA098710. The ATBC study is supported by NIH contracts N01-CN-45165, N01-RC-45035 and N01-RC-37004. F.R.S. is supported by an NRSA training grant (T32 CA 09001). P.F. is supported by a UK Engineering and Physical Sciences Research Council Grant (GR/S18786). M.M. is supported by the Wellcome Trust. N.O., R.B.H., S.W., K.Y., N.C., M.T., J.F.F., R.H., S.J.C. and G.T. are supported by the Intramural Research Program of the National Cancer Institute (US National Institutes of Health, Department of Health and Human Services).
The authors declare no competing financial interests.
Distribution of genotype counts and frequencies in cases and controls. (PDF 13 kb)
Results for single SNPs for all models tested. (PDF 15 kb)
Results for two-SNP model for all models tested and age and case status for single-SNP and two-SNP models. (PDF 96 kb)
Population-attributable risks. (PDF 10 kb)
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The relationship between KLK3 rs17632542 and PRNCR1 rs16901979 polymorphisms with susceptibility to prostate cancer
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