Large-scale fine mapping of the HNF1B locus and prostate cancer risk

Division of Cancer Epidemiology and Genetics, Department of Health and Human Services, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892-7240, USA.
Human Molecular Genetics (Impact Factor: 6.39). 06/2011; 20(16):3322-9. DOI: 10.1093/hmg/ddr213
Source: PubMed


Previous genome-wide association studies have identified two independent variants in HNF1B as susceptibility loci for prostate cancer risk. To fine-map common genetic variation in this region, we genotyped 79 single
nucleotide polymorphisms (SNPs) in the 17q12 region harboring HNF1B in 10 272 prostate cancer cases and 9123 controls of European ancestry from 10 case–control studies as part of the Cancer
Genetic Markers of Susceptibility (CGEMS) initiative. Ten SNPs were significantly related to prostate cancer risk at a genome-wide
significance level of P < 5 × 10−8 with the most significant association with rs4430796 (P = 1.62 × 10−24). However, risk within this first locus was not entirely explained by rs4430796. Although modestly correlated (r2= 0.64), rs7405696 was also associated with risk (P = 9.35 × 10−23) even after adjustment for rs4430769 (P = 0.007). As expected, rs11649743 was related to prostate cancer risk (P = 3.54 × 10−8); however, the association within this second locus was stronger for rs4794758 (P = 4.95 × 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 five SNPs (rs4430796, rs7405696, rs4794758, rs1016990
and rs3094509) together comprise the best model for risk in this region. This study demonstrates a complex relationship between
variants in the HNF1B region and prostate cancer risk. Further studies are needed to investigate the biological basis of the association of variants
in 17q12 with prostate cancer.

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    • "Some men with the HNF1B mutations have malformations in the reproductive tract including epididymal cysts, agenesis of the vas deferens, or infertility due to abnormal spermatozoa [35]. More recently, genetic variants in the HNF1B were implicated in the prostate [36, 37] and endometrial [38, 39] cancer risks. It was reported [40] that different HNF1B isoforms were expressed in prostate tumors versus normal prostate tissue, thus providing functional evidence for a potential role of this gene in PCa. "
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