Mutation analysis of the MSMB gene in familial prostate cancer.

Prostate cancer (PrCa) is the most common cancer in men in the western world, with 34 000 new cases every year and a lifetime risk of 1 in 14 in the United Kingdom (Cancer Research UK Factsheets, 2008). However, its aetiology remains poorly understood. The substantial worldwide variation in incidence rates suggests that there are lifestyle risk factors, but none have been identified definitively. Apart from demographic factors, the only well-established risk factor for PrCa is family history. The risk of the disease in first-degree relatives of cases is approximately twice that of the general population (Carter et al, 1992; Goldgar et al, 1994; Eeles, 1999; Hemminki and Czene, 2002; Gronberg, 2003; Edwards and Eeles, 2004). Familial risk is four-fold greater amongst close relatives of cases under 60-years old. Men with two or more affected relatives are at even higher risk. Analyses of the Nordic twin registries show higher risks in monozygotic compared with dizygotic twins, thereby supporting the hypothesis that much familial aggregation is due to genetic factors rather than shared lifestyle factors (Lichtenstein et al, 2000). Epidemiological studies consistently demonstrate aggregation of PrCa in families, consistent with a multi-genetic origin. To identify some of the multiple susceptibility loci we recently carried out a genome-wide association study (GWAS) of ∼550 000 single base pair genetic variants (SNPs) in 1854 PrCa cases and 1894 controls. Seven new susceptibility loci were validated in a further set of 3650 PrCa cases and 3940 controls containing several plausible candidate genes, one of which was on chromosome 10 (Eeles et al, 2008). Single base pair genetic variants rs10993994 and rs7920517 lie within an LD block of ∼100 kb on chromosome 10, containing the β-microseminoprotein beta gene, MSMB. The most strongly associated SNP, rs10993994, lies 2 bp upstream of the transcription start site of MSMB. This association was also reported by the CGEM study (Thomas et al, 2008). MSMB codes for PSP94, a prostatic secretory protein, synthesised almost exclusively in the prostate gland and it is the major constituent of seminal plasma. PSP94 functions in growth regulation and induction of apoptosis in PrCa cells (Garde et al, 1999) and, as it leaks into the blood, its serum level can be measured. There is a correlation between a reduced level of PSP94 and PrCa progression (Reeves et al, 2006; Bjartell, 2007), after radical prostatectomy. Thus, it is clear that the regulation of the expression of MSMB is a key element in PrCa development and any sequence variant, which has an effect on the level of MSMB gene expression would be a good candidate for a causal variant. The location of the rs10993994 and the strength of the association (P=10−17) raise the possibility that this SNP may be causally related to disease risk, although this remains to be proven. However, GWAS are designed to tag common variants, and associations mediated by rare variants may have been missed. In order to establish the contribution of variants at this locus to familial PrCa and to explore the possibility that there may be additional disease-associated variants in the MSMB gene, we re-sequenced the genomic sequence of the MSMB gene including a ∼1500 bp region upstream of the transcription start site in 192 PrCa cases with strong family history of the disease.