40-50% of CaP cases may be linked to genetic factors. Rare, highly penetrant genes may account for 5-10% of CaP cases. One must consider both the maternal and paternal lineage, she said. CaP risk is associated with the number of affected relatives, brothers as well as fathers and early age of CaP diagnosis in relatives. Relative risk of CaP according to family history increases from 2.4 with a brother with CaP to 5 for a person having 2 or more first degree relatives with CaP. In 1995 the NCI began funding a family based study of inherited CaP susceptibility. There are more than 4,000 men enrolled. Linkage studies are used to identify rare genes, and association studies are used for more common, but less penetrant variants. Association studies need large numbers of participants and controls. She identified 17q21-22 as a marker in families and it is close in location to the BRCA1 gene. This observation was based upon 147 families.
About six prostate cancer susceptibility genes were initially identified, but none seemed to be the ideal candidate gene. Nine additional genes are identified by linkage signals, although reproducibility has been problematic. PSA screening has led to an increase in the diagnosis of sporadic cases, making identification of familial cases more difficult, she pointed out. There is also locus heterogeneity and hereditary CaP is indistinguishable from sporadic CaP. Likely there are several genes that are mutated in a small fraction of CaP families.
Association studies are used to identify more common, but less penetrant genes. Genome-wide association studies examine >50,000 SNPs and over 30 SNPs have found that consistently are associated with CaP. The risk elevation for each SNP is small, at <1.5-fold. Young men with CaP have more CaP risk alleles, she showed. Men under age 50 years had more than 12 risk alleles.
She said that men from families with CaP should be referred to a cancer genetics clinic, although there is no specific test available for hereditary CaP. The relative risk of CaP in men under age 65 with known BRCA1 or BRCA2 mutations is 1.8 and 7.3, respectively. For all ages with BRCA2, it is a RR = 4.7. The search continues for rare CaP susceptibility genes, she concluded.
Presented by Kathleen A. Cooney, MD, FACP at the American Urological Association (AUA) Annual Meeting - May 14 - 19, 2011 - Walter E. Washington Convention Center, Washington, DC USA
Reported for UroToday by Christopher P. Evans, MD, FACS, Professor and Chairman, Department of Urology, University of California, Davis, School of Medicine.