Abstract B54: Prostate cancer screening characteristics in high-risk men with genetic risk markers at 8q and 17q
Authors: Williams Kara , Ruth Karen , Hughes Lucinda , Giri Veda 
Published: May 2012

Abstract
B54

Background
Men with a family history (FH) of prostate cancer (PCA) and African American (AA) men are at 2 to 7-fold increased risk for the disease. Assessing risk for PCA in these high-risk men has been challenging due to the lack of available genetic testing. Recently, five genetic single nucleotide polymorphisms (SNPs) at chromosomal loci 8q and 17q (rs1859962, rs6983267, rs4430796, rs1447295, and rs16901979) were found to have a cumulative increased association with PCA in multiple studies. These genetic variants need to be characterized in screening populations to determine their utility in the early detection of PCA. The Prostate Cancer Risk Assessment Program (PRAP) at Fox Chase Cancer Center is a prospective screening program for high-risk men. Currently there are over 700 participants, and 60% are AA. This study evaluates the clinical characteristics of high-risk men carrying these risk SNPs and time to PCA diagnosis based on the presence of these 8q/17q risk markers.

Methods
Eligibility for PRAP includes men ages 35-69 years with one first degree relative with PCA, two second degree relatives with PCA on the same side of the family, any AA man regardless of FH of PCA, and men with BRCA1/2 mutations. Current criteria for biopsy include PSA &gt; 2.0 ng/mL, PSA 1.5-2.0 ng/mL with free PSA &lt; 25%, any abnormality on digital rectal examination, or PSA velocity of 0.75 ng/mL/year. All biopsies are 12-core under transrectal ultrasound guidance with additional cores taken at physician discretion. Genotyping of SNPs rs1859962, rs6983267, rs4430796, and rs1447295 was performed using the Taqman® SNP Genotyping Assay (Applied Biosystems) per manufacturer’s instructions. Pyrosequencing methods were used for SNP rs16901979 as Taqman assays did not produce reliable results. Standard statistical methods were used to determine allele and genotype distributions by race. Cox models were used to determine time to PCA diagnosis by number of high risk SNPs.

Results
Genotypes for all five SNPs was able to be determined on 633 PRAP participants of whom 60% were AA. Average follow-up for these participants in PRAP has been 3-4 years. There was a statistically significant difference in the baseline distribution of risk alleles and risk genotypes of these five SNPs within self-reported race groups (p&lt;0.0001). Age-adjusted baseline PSA differed significantly among high-risk Caucasian PRAP participants, with a higher baseline PSA in men carrying the risk genotype at rs4430796 vs. men without the risk genotype at this SNP (p=0.0063). More AA men were found to carry 2-3 and 4-5 risk-associated SNPs than high-risk Caucasian men in PRAP (p&lt;0.0001). Time to PCA diagnosis was evaluated in 332 PRAP participants who had at least one follow-up visit. Among the 210 AA participants with at least one follow-up visit, there was a trend for earlier time to PCA diagnosis for those with 4-5 risk SNPs vs. 0-1 risk SNPs (p=0.059). Hazard ratios for PCA risk increased substantially in AA men with 4-5 SNPs vs. 2-3 SNPs (4.28 vs. 1.84), although this was not significant. No trends were observed for high-risk Caucasian men regarding time to PCA diagnosis.

Conclusions
Five genetic risk markers at 8q/17q may be useful in tailoring screening approaches in high-risk men, particularly AA men. Further follow-up is needed to firmly determine how these risk markers influence time to PCA diagnosis.
Citation Information: Cancer Prev Res 2008;1(7 Suppl):B54.