Prostate Cancer, Hereditary, 13

A number sign (#) is used with this entry because single-nucleotide variation in the promoter region of the MSMB gene (157145) has been associated with the development of prostate cancer.

For a general discussion of hereditary prostate cancer, see 176807.

In a large 2-stage genomewide association study of prostate cancer, Thomas et al. (2008) identified a SNP, rs10993994 (157145.0001), in the proximal promoter of the MSMB gene on chromosome 10q11.2 that was significantly associated with prostate cancer risk (7.31 x 10(-13)). The MSMB gene encodes beta-microseminoprotein (MSP), a member of the immunoglobulin binding factor family synthesized by epithelial cells of the prostate and secreted into seminal plasma. MSP and its binding protein in serum, PSPBP (PI16), have been proposed as serum markers for early detection of high grade prostate cancer. Although its expression has been noted in both normal and neoplastic prostate tissue, MSMB can be silenced by EZH2 (601573) in advanced, androgen-insensitive prostate cancer. Buckland et al. (2005) found that the rs10993994 SNP of MSMB functionally altered in vitro gene expression.

Eeles et al. (2008) conducted a genomewide association study using blood DNA samples from 1,854 individuals with clinically detected prostate cancer diagnosed at or before the age of 60 years or with a family history of disease, and 1,894 population-screened controls with a low prostate-specific antigen (PSA; see 176820) concentration (less than 0.5 ng/ml). Analysis of these samples for 541,129 SNPs was performed using the Illumina Infinium platform. Initial putative associations were confirmed using a further 3,268 cases and 3,366 controls. Eeles et al. (2008) identified a SNP in the MSMB gene, rs10993994, that was significantly associated with prostate cancer (8.7 x 10(-29)). The SNP rs10993994 is 2 basepairs upstream of the transcription start site of MSMB. The risk allele, T, affects multiple predicted binding sites for transcription and splicing factors. Putative androgen and estrogen binding sites lie less than 50 kb upstream from this SNP. Loss of expression of MSMB is associated with recurrence after radical prostatectomy (Reeves et al., 2006).

By fine-mapping analysis of a 65-kb region on chromosome 10q including rs10993994 in 6,118 prostate cancer cases and 6,105 controls of European origin, Lou et al. (2009) found rs10993994 remained the SNP most strongly associated with prostate cancer risk (p = 8.8 x 10(-18); heterozygous odds ratio (OR) of 1.20, homozygous OR of 1.64). Lou et al. (2009) stated that the SNP was located at position -57. In vitro functional analysis showed that the T allele was associated with decreased transcriptional activity and that the C allele preferentially bound to the CREB transcription factor (123810). Analysis of tumor cell lines with a CC or CT genotype revealed a higher level of MSMB gene expression compared to cell lines with a TT genotype. Lou et al. (2009) suggested that regulation of MSMB expression is a plausible mechanism accounting for the association with prostate cancer identified at this locus.

Yeager et al. (2009) sequenced a 97-kb region of chromosome 10q11.2 including the area surrounding the MSMB gene and the NCOA4 gene (601984) in 70 unrelated individuals, including 36 with prostate cancer. They identified a 51-kb block of linkage disequilibrium (LD) containing rs10993994 and the proximal promoter of the MSMB gene. No additional variants in LD with rs10993994 were identified, suggesting that this is the probable variant that accounts for the association with prostate cancer. In total, 241 novel polymorphisms were identified in the 97-kb region, but none were in the exons of the MSMB gene. No polymorphic sites were found in the first 6 exons of the NCOA4 gene, but several were observed in exons 7 through 10.