Prostate Cancer, Hereditary, 11

<p>For a general discussion of hereditary prostate cancer, see 176807.p> Mapping <p>Gudmundsson et al. (2007) performed a genomewide association scan of 1,501 Icelandic men with prostate cancer and 11,290 controls, followed by 3 case-control replication studies in individuals from the Netherlands, Spain, and Chicago and found an association between prostate cancer and the A allele of rs4430796 in intron 2 of the TCF2 gene (HNF1B; 189907) (p = 1.4 x 10(-11) for the combined studies). The authors noted that the risk conferred by this variant is modest (allele odds ratio, 1.22), but because it is common, the population-attributable risk is substantial. p><p>In a large genomewide association study of prostate cancer, Thomas et al. (2008) confirmed the association found by Gudmundsson et al. (2007) with the A allele of the SNP rs4430796 (9.58 x 10(-10)). p><p>In a large 2-stage genomewide association study of prostate cancer involving white participants from the United Kingdom and Australia screening 541,129 SNPs, Eeles et al. (2008) found 6 strongly associated SNPs on chromosome 17 (P less than 10(-6)). Four of these were at 17q12, with the strongest association observed for rs7501939 in the HNF1B gene (OR = 0.71, P = 10(-12)). A P value of 8.3 x 10(-12) was observed for the SNP rs4430796. p><p>Sun et al. (2008) carried out a fine mapping study of the HNF1B gene at 17q12 in 2 study populations and identified a second locus associated with prostate cancer risk, approximately 26 kb centromeric to the first known locus (rs4430796); these loci are separated by a recombination hotspot. Sun et al. (2008) confirmed the association with a SNP in the second locus (rs11649743) in 5 additional populations, with P = 1.7 x 10(-9) for an allelic test of the 7 studies combined. The association at each SNP remained significant after adjustment for the other. p><p>By targeted SNP analysis of 542 non-Hispanic men with prostate cancer from 403 families and 473 unaffected men, Levin et al. (2008) found that the A allele of rs4430796 in the HNF1B gene on 17q12 was significantly associated with prostate cancer, particularly among men diagnosed before age 50 years (p = 0.006 with an odds ratio of 1.92), but not later age (p = 0.118). Homozygous carriers of the A allele had a 3.70-fold increased risk of developing prostate cancer at an early age compared to noncarriers. The results confirmed the prostate cancer association with SNPs on chromosome 17q12, and indicated that this locus may also play a role in hereditary prostate cancer with early onset. p><p>Berndt et al. (2011) genotyped 79 SNPs in the 17q12 region harboring HNF1B in 10,272 patients with prostate cancer and 9,123 controls of European descent. The most significant association was with rs4430796 (p = 1.62 x 10(-24)). Risk was also associated with rs7405696 (p = 9.35 x 10(-23)), even after adjustment for rs4430796 (p = 0.007). At the second locus in this region, prostate cancer risk was associated with rs11649743 (p = 3.54 x 10(-8)), but an even stronger association was found for rs4794758 (p = 4.95 x 10(-10)), which explained all of the risk observed with rs11649743 when both SNPs were included in the same model (p = 0.32 for rs11649743; p = 0.002 for rs4794758). Sequential conditional analyses indicated that 5 SNPs (rs4430796, rs7405696, rs4794758, rs1016990, and rs3094509) together comprised the best model for risk in this region. The study demonstrated a complex relationship between variants in the HNF1B region and prostate cancer risk. p>