PD15-06 GENETIC RISK SCORE DIFFERENTIATES INHERITED RISK AMONG RELATIVES OF PATIENTS WITH HEREDITARY PROSTATE CANCER

INTRODUCTION AND OBJECTIVES: Clinical guidelines for prostate cancer (PCa) recommend targeted screening for men with a family history of the disease. However, family history assigns equivalent risk to relatives based upon the degree of relationship to affected family members. Recent genetic studies have identified single nucleotide polymorphisms (SNPs) that can be used to calculate a genetic risk score (GRS) to determine PCa risk. We examined whether GRS can stratify PCa risk among high-risk hereditary PCa families. METHODS: Family members of patients with hereditary PCa were recruited and genotyped for 17 PCa risk-associated SNPs. A GRS was calculated for each family member using weighted odds ratios (ORs) and allele frequencies for each SNP obtained from previously published meta-analyses. A GRS of 1.0 indicates an average risk of developing PCa in the general population, while a GRS greater or less than 1.0 indicates increased or decreased disease risk, respectively. The generalized estimating equation (GEE) model was used to account for the relatedness of men within each family. Univariate and multivariate analyses were performed to compare the distribution of GRSs amongst affected and unaffected family members of similar and different degrees of relation. RESULTS: Data was available for 789 family members of probands, of which 552 had PCa and 237 did not. There was a wide range of GRSs among family members with the same degree of relationship to a proband. The interquartile range (IQR) for GRSs among first-degree relatives ranged from 0.76 to 1.84. The median GRS was significantly higher among first-degree relatives compared to secondand third-degree relatives (GRS 1.20 vs. 1.09 vs. 1.00, pu003c0.001). GRSs among affected firstand second-degree relatives were significantly higher than unaffected relatives (p1⁄40.04 and p1⁄40.01, respectively). On univariate analysis, degree of family relationship (OR 1.85, pu003c0.001) and GRS (OR 1.52, pu003c0.001) were both independent predictors of PCa. Multivariate analysis controlling for degree of relationship demonstrated that GRS was a significant and independent predictor of PCa (OR 1.52, 95% CI: 1.15-2.01). CONCLUSIONS: GRS can augment family history in differentiating inherited PCa risk among relatives of PCa patients. While prospective validation studies are required, this information can help provide guidance for these relatives in determining initiation and frequency of PCa testing.