989 A RARE GENETIC VARIANT ON CHROMOSOME 8Q24 THAT CONFERS A SIGNIFICANTLY GREATER RISK OF PROSTATE CANCER

Abstract

INTRODUCTION AND OBJECTIVES: Genome wide association studies have identified numerous single nucleotide polymorphisms (SNPs) that individually increase the risk of prostate cancer to a very modest extent ( 1.2-1.3 fold). Advancements in sequencing technology have enabled the identification of new genetic variants that are rare but have a much more robust association with prostate cancer susceptibility. In collaboration with deCODE Genetics, we performed whole genome sequencing and identified a new variant on chromosome 8q24 (rs18814048). We herein sought to report the association of this SNP with prostate cancer risk and associated pathologic characteristics. METHODS: A total of 4295 Caucasian men, including 1975 (46%) men with prostate cancer, were identified from a prospective prostate cancer genetic database and genotyped for rs18814048. Statistical analyses were performed to compare the frequency among cases and controls, and the relationship to pathologic tumor features at the time of radical prostatectomy. RESULTS: The mean age in the study population was 60 years with a median PSA of 5.3 ng/ml. Overall, 1.16% of men with prostate cancer were carriers for the risk allele compared to only 0.44% of healthy controls (OR 3.14, 95% CI 1.85-5.35). There was no significant difference in the proportion with a prostatectomy Gleason score 7 (OR 1.4, 95% CI 0.77-2.56, p 0.26) or non-organ confined disease (OR 1.66, 95% CI 0.86-3.22, p 0.13). CONCLUSIONS: SNP rs188140481 is a novel variant which is much less common but confers a much greater risk of prostate cancer than those previously identified through genome-wide association studies. While larger studies are required to evaluate associations with adverse pathologic features, our present results emphasize the importance of whole genome sequencing to more fully elucidate the genetics of prostate cancer susceptibility.