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Evaluation of PPP2R2A as a prostate cancer susceptibility gene: a comprehensive germline and somatic study.

ABSTRACT: PPP2R2A, mapped to 8p21.2, codes for the ? isoform of the regulatory B55 subfamily of protein phosphatase 2 (PP2A). PP2A is one of the four major serine/threonine phosphatases and is implicated in the negative control of cell growth and division. Because of its known functions and location within a chromosomal region where evidence for linkage and somatic loss of heterozygosity was found, we hypothesized that either somatic copy number changes or germline sequence variants in PPP2R2A may increase prostate cancer (PCa) risk. We examined PPP2R2A deletion status in 141 PCa samples using Affymetrix SNP arrays. It was found that PPP2R2A was commonly (67.1%) deleted in tumor samples, including a homozygous deletion in three tumors (2.1%). We performed a mutation screen for PPP2R2A in 96 probands of hereditary prostate cancer families. No high risk mutations were identified. In addition, we re-analyzed 10 SNPs of PPP2R2A in sporadic PCa cases and controls. No significant differences in the allele and genotype frequencies were observed among either PCa cases and controls or PCa aggressive and non-aggressive cases. Taken together, these results suggest that a somatic deletion rather than germline sequence variants of PPP2R2A may play a more important role in PCa susceptibility.

SUBMITTER: Cheng Y

PROVIDER: S-EPMC3722858 | biostudies-literature | 2011 Jul

REPOSITORIES: biostudies-literature

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Evaluation of PPP2R2A as a prostate cancer susceptibility gene: a comprehensive germline and somatic study.

Cheng Yu Y Liu Wennuan W Kim Seong-Tae ST Sun Jishan J Lu Lingyi L Sun Jielin J Zheng Siqun Lilly SL Isaacs William B WB Xu Jianfeng J

Cancer genetics 20110701 7

PPP2R2A, mapped to 8p21.2, codes for the α isoform of the regulatory B55 subfamily of protein phosphatase 2 (PP2A). PP2A is one of the four major serine/threonine phosphatases and is implicated in the negative control of cell growth and division. Because of its known functions and location within a chromosomal region where evidence for linkage and somatic loss of heterozygosity was found, we hypothesized that either somatic copy number changes or germline sequence variants in PPP2R2A may increas ...[more]

PMID: 21872824

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Project description:BACKGROUND:It is unclear whether germline breast cancer susceptibility gene mutations affect breast cancer related outcomes. We wanted to evaluate mutation patterns in 20 breast cancer susceptibility genes and correlate the mutations with clinical characteristics to determine the effects of these germline mutations on breast cancer prognosis. METHODS:The study cohort included 480 ethnic Chinese individuals in Taiwan with at least one of the six clinical risk factors for hereditary breast cancer: family history of breast or ovarian cancer, young age of onset for breast cancer, bilateral breast cancer, triple negative breast cancer, both breast and ovarian cancer, and male breast cancer. PCR-enriched amplicon-sequencing on a next generation sequencing platform was used to determine the germline DNA sequences of all exons and exon-flanking regions of the 20 genes. Protein-truncating variants were identified as pathogenic. RESULTS:We detected a 13.5% carrier rate of pathogenic germline mutations, with BRCA2 being the most prevalent and the non-BRCA genes accounting for 38.5% of the mutation carriers. BRCA mutation carriers were more likely to be diagnosed of breast cancer with lymph node involvement (66.7% vs 42.6%; P?=?0.011), and had significantly worse breast cancer specific outcomes. The 5-year disease-free survival was 73.3% for BRCA mutation carriers and 91.1% for non-carriers (hazard ratio for recurrence or death 2.42, 95% CI 1.29-4.53; P?=?0.013). After adjusting for clinical prognostic factors, BRCA mutation remained an independent poor prognostic factor for cancer recurrence or death (adjusted hazard ratio 3.04, 95% CI 1.40-6.58; P?=?0.005). Non-BRCA gene mutation carriers did not exhibit any significant difference in cancer characteristics or outcomes compared to those without detected mutations. Among the risk factors for hereditary breast cancer, the odds of detecting a germline mutation increased significantly with having bilateral breast cancer (adjusted odds ratio 3.27, 95% CI 1.64-6.51; P?=?0.0008) or having more than one risk factor (odds ratio 2.07, 95% CI 1.22-3.51; P?=?0.007). CONCLUSIONS:Without prior knowledge of the mutation status, BRCA mutation carriers had more advanced breast cancer on initial diagnosis and worse cancer-related outcomes. Optimal approach to breast cancer treatment for BRCA mutation carriers warrants further investigation.

Project description:IntroductionGermline variants in androgen metabolism genes may influence clinical response to androgen deprivation therapy (ADT) in advanced prostate cancer. We sought to investigate the prognostic significance of germline variants in androgen metabolism genes with respect to overall survival (OS) after ADT, and to associate germline variants with tumor genomic features.MethodsGermline and somatic whole-genome sequencing (WGS) data were evaluated in a cohort of 101 men with metastatic castration-resistant prostate cancer (mCRPC). Survival analyses were performed to identify polymorphisms associated with impaired OS after primary ADT. Germline variants found to be prognostic of OS were associated with tumor somatic DNA-sequence alterations based on WGS performed on paired metastasis biopsies from the same 101 patients. Gene set enrichment analysis was performed based on tumor RNA-sequencing data to identify genomic pathways differentially expressed in patients with germline variants.ResultsA comprehensive literature review identified 17 candidate polymorphisms in nine androgen metabolism genes that have been previously shown to have an association with response to ADT in prostate cancer. Of these, the variant rs1856888 allele located 13 kb upstream of HSD3B1 was found to be significantly associated with impaired OS (P = 0.029). Variant rs1856888 was commonly co-inherited with the well-characterized HSD3B1(1245A>C) polymorphism, and there was a trend toward shorter median OS in patients with HSD3B1(1245A>C) compared with homozygous wild-type patients (P = 0.052). While HSD3B1 germline variants were not associated with common somatic tumor DNA alterations, they were associated with increased tumor expression of cell proliferation and cell cycle genes.ConclusionsThis study presents a comprehensive assessment of germline variants in androgen metabolism genes and highlights HSD3B1 polymorphisms as prognostic of OS after ADT and associated with an aggressive gene expression tumor profile in mCRPC.

Dataset Information

Evaluation of PPP2R2A as a prostate cancer susceptibility gene: a comprehensive germline and somatic study.

Publications

Evaluation of PPP2R2A as a prostate cancer susceptibility gene: a comprehensive germline and somatic study.

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