Abstract 2769: Evaluation of PPP2R2A as a prostate cancer susceptibility gene: Comprehensive germline and somatic study

Abstract

Abstract PPP2R2A, a gene mapped to 8p21.2, encodes α isoform of the regulatory B55 subfamily of the protein phosphatase 2 (PP2A). PP2A is one of the four major Ser/Thr phosphatases, and is implicated in the negative control of cell growth and division. Because of its known functions and its location within a chromosomal region where evidence for linkage and somatic loss of heterozygosity were found, we hypothesized that either germline sequence variants or somatic copy number changes in PPP2R2A may increase prostate cancer (PCa) risk. To address this, we first sequenced PPP2R2A in 96 probands of hereditary prostate cancer (HPC) families recruited at John Hopkins Hospital; each family had at least three first-degree relatives affected with prostate cancer. Twenty-five germ-line variants were identified in this analysis, including 15 known SNPs and 10 new sequence variants. Most new sequence variants were rare, except 2 new sequence variants with minor allele frequency (MAF) ≥ 0.05 (−482T/C MAF=0.072 and -78C/G MAF=0.058). Thereafter, it was less likely that these sequence variants of PPP2R2A would be co-segregated with PCa. Second, to see if there are any genetic variants in PPP2R2A associated with sporadic PCa, we analyzed 10 SNPs of 15 known SNPs that span the complete PPP2R2A gene in Cancer Genetic Markers of Susceptibility (CGEMS, 737 cases and 1,105 controls) and in Cancer of the Prostate in Sweden (CAPS, 498 cases and 494 controls) from a Sweden population, as genotypes of these 10 SNPs had already been available in both studies. No consistent significant differences in the allele and genotype frequencies were observed among these sporadic PCa cases and controls. Finally, we examined the deletion status in 141 clinical PCa samples from John Hopkins using Affymetrix 6.0 SNP arrays. With the allele-specific analysis of intensities from all paired tumor and normal tissue samples, it was found that PPP2R2A was commonly (67.1%) deleted in these tumor samples including a homozygous deletion in 3 tumors (2.1%). These results suggest that somatic deletion rather than germline sequence variants of PPP2R2A may play a more important role in prostate cancer susceptibility. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2769. doi:10.1158/1538-7445.AM2011-2769