Whole exome sequencing of 2126 African American prostate cancer cases and controls from the Multiethnic Cohort. K. A. Rand1,4, N. Rohland2,3,4, A. Tandon2,3, R. Do3, X. Sheng1, D. V. Conti1, B. E. Henderson1, C. A. Haiman1,4, D. Reich2,3,4 1) Department of Preventive Medicine, Keck School of Medicine and Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA 90033, USA; 2) Department of Genetics, Harvard Medical School, Boston, MA 02115, USA; 3) Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA 02142, USA; 4) These authors contributed equally to this work.

   Prostate cancer disproportionately affects African American men, with more than a two-fold increased risk when compared to other racial/ethnic populations. Previous studies have identified common genetic variants associated with prostate cancer, as well as regions of the genome that explain a portion of the excess risk observed in African Americans; however, a large proportion of the heritability of prostate cancer remains unexplained. Furthermore, these studies have been limited in their ability to adequately assess the contribution of risk from rare variants (minor allele frequency (MAF) < 0.01), which have been hypothesized to have large effects. Whole exome sequencing provides the opportunity to directly examine rare functional mutations within the coding region of the genome. To further explore both common and rare genetic variation associated with prostate cancer, we sequenced the exomes of 2126 African American prostate cancer cases and controls from the Multiethnic Cohort. A barcoded library preparation was utilized, allowing for highly multiplexed target enrichment, with a 51Mb targeted region encompassing 20,965 genes and 334,278 exons. On average, these individuals were sequenced at 8.2x coverage (+/- 4.2x). After initial filtering, we identified 486,143 variants in coding regions, with 44,366 singletons. We observed 286,015 nonsynonymous, 188,186 synonymous, 7,154 stopgain, and 303 stoploss variants, respectively. Of the variants with a MAF > 0.01, 97% have been previously identified in the 1000 genomes project. The rare variants (MAF < 0.01) include 58% of the observed splicing sites and 61% of the nonsynonymous variants. In the preliminary association analysis, we identified 36 SNVs with a p-value < 5x10-4, and are currently sequencing another 2000 prostate cancer cases and controls that will be included in the final analysis. Results from this analysis may shed light on the effect of rare variants on prostate cancer risk, as well as provide insight into the genetic basis for the observed racial/ethnic disparity in disease incidence.

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