Identification of Novel Inherited Genetic Markers for Aggressive PCa in European and African Americans Using Whole Genome Sequencing.

摘要

Prostate cancer (PCa) is the most common cancer and the second leading cause of cancer death among men in the US. While most PCa patients have an indolent form of the disease that may not even require treatment, about 10-15% of PCa patients have an aggressive form that may progress to metastases and death, thus requiring intensive treatment. Several clinical variables such as PSA levels, Gleason grade and TNM stage are good predictors for disease with poor clinical outcomes; however, their predictive performance needs to be improved. Our inability to reliably distinguish between these two forms of PCa, early on in the course of the disease has resulted in the over-treatment of many and under treatment of some. The identification of additional markers, including genetic variants will improve our ability to distinguish aggressive from indolent forms of PCa and to better understand the racial disparity of PCa that exists between European Americans (EA) and African Americans (AA). In this DOD proposal, we hypothesized that multiple rare sequence variants in the genome may increase aggressive PCa risk. Through a GWAS of rare variants based on three existing populations from Johns Hopkins Hospital, Michigan and CAPS population from Sweden, with a total of 1,919 PCa cases, including 470 aggressive PCa cases and 1,449 indolent PCa cases using Illumina's Human Exome BeadChip, we have identified and confirmed several novel rare variants in the INPP5D gene and HINFP gene that are associated with aggressive PCa in both Caucasians and African American men. The newly identified variants can provide more insight into the etiology of aggressive PCa and provide potential effective targets for therapy of aggressive PCa.