Abstract C039: Investigation of a prostate cancer genetic susceptibility candidate region on chromosome 5 in African Americans

Abstract

Abstract There are well documented, marked racial disparities in prostate cancer (PCa) incidence and mortality in the United States between African American (AA) and European American (EA) men. These disparities cannot be fully explained by differences in screening or treatment differences by race, and other environmental and biological risk factors have not been well characterized. We hypothesize that racial differences in the distribution of genetic risk factors may contribute to the observed disparities. We previously identified a region on chromosome 5q35 via admixture mapping that is associated with PCa in AA men (Bock 2009). Preliminary analyses in this region suggested two loci involved in chromatin regulation, and several genes including COL23A1, TSPAN17, and GRM6. These are genes that have not been well characterized in the literature, however hints of their role in PCa can be found within previous expression studies. Here, we examine the region on chromosome 5q35 in greater depth to first confirm the observed admixture and to leverage the admixture signal within that region to identify novel variants associated with risk of prostate cancer in African Americans. To achieve the first goal, we estimated genome-wide and local ancestry across chromosome 5 in African American subjects from the Multiethnic Cohort (MEC) and an independent case control study from the Barbara Ann Karmanos Cancer Institute (KCI). Our results validated the significance of the admixture (p=7.87*10-6). However, the ancestry odds ratio from the MEC study was in the opposite direction in comparison to our original discovery analysis. Despite this difference, after combining studies via meta-analysis, we still retained a significant admixture peak on the distal portion of the chromosome 5q (p=5.47*10-4), which stretched from 152-180Mb. Overall, this effect showed that increasing European ancestry at this locus was associated with increased risk of prostate cancer. Additionally, our admixture meta-analysis uncovered a secondary peak (p=3.66*10-4) from 64-96Mb, where increased risk of prostate cancer was again associated with increasing European ancestry at this locus. We also performed association testing using the MIXSCORE approach, which is a combined test of genotype and local ancestry association. Our most significant association results were located within our primary admixture association peak, and they clustered around a locus at 173 Mb. The lead single nucleotide polymorphism (SNP) within this region was rs6885032 (MIXSCORE p=7.83*10-4). Interestingly, this SNP was identified in a genome-wide association analysis as associated with height, and a recent meta-analysis of studies from the literature confirmed an association between height and prostate cancer risk. Furthermore, this SNP was also identified as an expression quantitative trait locus (p=3.30*10-9) in the Genotype-Tissue Expression project. This convergence of findings suggests a possible mechanism for this variant on prostate cancer risk. Citation Format: Albert M Levin, Gregory Dyson, Julie L Boerner, Julie J Ruterbusch, Cathryn H Bock. Investigation of a prostate cancer genetic susceptibility candidate region on chromosome 5 in African Americans [abstract]. In: Proceedings of the Twelfth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2019 Sep 20-23; San Francisco, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(6 Suppl_2):Abstract nr C039.