Abstract 924: Identification of somatic mutations of the PPP2R1A gene in subtypes of endometrial and ovarian carcinomas

Abstract

Abstract Somatic mutations in PPP2R1A have been found at low frequencies in lung, breast cancer and melanoma and most recently through whole-exome sequencing in ovarian clear cell carcinoma. We examined whole-transcriptome sequencing data from ovarian clear cell carcinomas (OCCC) and identified a cluster of mutations in exon 5 of PPP2R1A. The protein phosphatase 2, regulatory subunit A, alpha (PPP2R1A, or PR65a) gene is the scaffolding subunit of the serine-threonine protein phosphatase 2A (PP2A) holoenzyme. PP2A is involved in growth and survival cellular pathways, and has been suggested to play a role as a tumor suppressor gene in some human cancers. The PP2A holoenzyme is made up of the A scaffolding subunit (isoforms α and β), the C catalytic subunit (isoforms α and β and multiple regulatory B subunits also with many isoforms. PPP2R1A is made up of 15 HEAT domains forming a horseshoe-like multi-helical structure that interacts with both the C and B subunits of PP2A. We have examined the frequency of PPP2R1A mutations across the spectrum of both ovarian and endometrial carcinomas. DNA from endometrial and ovarian subtypes was sequenced across exons 5 and 6 of PPP2R1A using PCR based Sanger sequencing, and somatic mutation status was verified by sequencing matched normal DNA. Targeted sequencing of PPP2R1A revealed somatic missense mutations in 36.7% (18 of 49) of endometrial high-grade serous primary tumors. This high frequency of mutations has not previously been reported and suggests a strong link to the pathology of this disease subtype. Mutations were also identified at a lower frequency of 4.9% (3 of 61) in endometrial endometrioid carcinomas, and ovarian primary tumors at 11.6% (5 of 43) in endometrioid, 4% (2 of 50) in clear cell, 0% (0 of 50) in high-grade serous and 0% (0 of 12) of low-grade serous carcinomas. These nucleotide missense mutations result in the modification of amino acid residues that are highly conserved within the intrarepeat helix of the HEAT domains of PPP2R1A. Previous mutation based biochemical studies have identified these amino acid residues as important in the interaction between the regulatory B subunit and PPP2R1A. This indicates a strong functional role of PPP2R1A in stabilization of the PP2A complex, and a probable role in cellular tumorgenesis. A closer survey of mutations found within PPP2R1A and the PP2A complex, as well as functional characterization of this pathway, may pave the way to defining biologically relevant pathways and targets within endometrial carcinomas, ultimately leading to improved patient-targeted therapies and survival. 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 924. doi:10.1158/1538-7445.AM2011-924