Abstract PO-202: Copy number variation (CNV) analysis identifies variants in 1p36 in African American and Caucasian hereditary prostate cancer cases
Authors: Williams Alan F. , Termine Kirsten W. , Waldron John , Sartor Oliver , Bailey-Wilson Joan , Mandal Diptasri 
Published: January 2022

Prostate cancer (PCa) is a common malignancy which affects 1 in 8 men. There is a significant racial disparity and African American (AA) males are more at risk for developing such cancers, at a rate of almost double compared to the males of European ancestry (EA). So far, not much is known about the role of germline copy number variations (CNVs) in this health disparity. Our previous work has shown several genetic regions with CNVs in both AA and EA hereditary prostate cancer (HPC) cases. The goal of this project was to detect germline CNVs in the targeted resequencing data spanning 9 Mb region in 1p36, that was previously identified by microarray and whole exome sequencing analyses. For this study, a total of 50 individuals were used, 25 AA and 25 EA men from HPC families. We have used three CNV calling algorithms: XHMM, CANOES, and GATK4. First, we focused on four PCa associated genes: NBPF1, NBL1, SRSF10, and RHD, that were previously identified in our study. In the current CNV analysis, XHMM identified deletions in NBPF1 in several samples in both AA and EA cases. GATK4 was unable to call any CNVs in this gene. NBL1 had no identified deletions in any tool, despite previous microarray data to the contrary. XHMM identified full deletions of SRSF10 in most of the cases, while GATK4 identified partial deletion in several cases from both ancestries, but more frequently in AA cases. Finally, a deletion was detected in RHD in only a few cases, and the deletion was confirmed by both XHMM and GATK4 algorithms. Deletion in RHD was more common in the EA population than the AA population. CANOES was unable to identify any variants within our regions of interest. We then expanded our search to other identified variants to identify regions commonly detected by the CNV calling algorithms. A region of deletion was detected in the CELA3A gene (reported to be downregulated in pancreatic and prostate cancer) and a region between AKR7L and AKR7A3 both of which are found to be frequently mutated in cancer cells. XHMM called the deletion of both of these regions at a much higher rate than GATK4: nearly in all our cases from the two ancestries, compared to only a few in GATK4 and CANOES. The few PCa cases who had deletions across all tools were always in the AA population. Altogether, this new analytical strategy establishes the usefulness of applying multiple CNV callers in identifying regions of potential interest, as well as verifying the results from previous studies of PCa. Results from this study may hold valuable information in finding potential biomarkers to address PCa health disparity in the future. Further validation of the identified variants is ongoing.

Citation Format: Alan F. Williams, Kirsten W. Termine, John Waldron, Oliver Sartor, Joan Bailey-Wilson, Diptasri Mandal. Copy number variation (CNV) analysis identifies variants in 1p36 in African American and Caucasian hereditary prostate cancer cases [abstract]. In: Proceedings of the AACR Virtual Conference: 14th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2021 Oct 6-8. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2022;31(1 Suppl):Abstract nr PO-202.