Infrequent mutations of the PPP2R1A and PPP2R1B genes in patients with ovarian cancer

Abstract

Abstract. Protein phosphatase 2, regulatory subunit A, α (PPP2R1A) and β (PPP2R1B) are paralogous subunits of the heterotrimeric protein phosphatase 2 (PP2A) holoenzyme that catalyzes the dephosphorylation of target substrate proteins. Subtype-specific PPP2R1A mutations have been frequently observed in ovarian and endometrial cancer. Mutations in the paralogous genes were frequently observed in human malignancies. Thus, the present study aimed to analyze the mutation frequencies of the paralogous PPP2R1A and PPP2R1B genes in patients with primary and secondary ovarian cancer. A total of 251 patients with primary (n=234) and secondary (n=17) ovarian cancer were analyzed for the presence of PPP2R1A and PPP2R1B mutations by direct sequencing. For PPP2R1A, a heterozygous, somatic mutation (c.771G>T, p.W257C) was identified in 1 out of 37 patients (2.7%) with primary ovarian endometrioid carcinoma. The mutant sample was that of a 46-year-old female, who was also diagnosed with ectopic endometriosis in the benign ovary. No PPP2R1A mutations were detected in the remaining 250 patients with ovarian cancer. For PPP2R1B, no mutations were detected in our samples. The results of this study suggested that PPP2R1A mutations are less common in Chinese patients with ovarian cancer when compared with European and American patients. Furthermore, our study also supported previous observations that PPP2R1B mutations were absent in ovarian cancer, suggesting that PPP2R1B mutations are not actively involved in the pathogenesis of ovarian cancer. IntroductionProtein phosphatase 2, regulatory subunit A, α (PPP2R1A) and β (PPP2R1B) are paralogous subunits of the heterotrimeric protein phosphatase 2 (PP2A) holoenzyme, which catalyzes the dephosphorylation of target substrate proteins (www.ensembl.org) (1). PPP2R1A and PPP2R1B belong to the Huntington-elongation-A subunit-TOR (HEAT) repeat protein family, and are required as scaffolds for the formation of the heterotrimeric PP2A complex (2). PPP2R1A and PPP2R1B each contain 15 tandemly repeated HEAT motifs. It has been previously demonstrated that the HEAT repeats 2-8 and 11-15 were involved in binding to the regulatory and catalytic subunits of PP2A, respectively (3). In addition, mutations located in the HEAT 2 and 11 motifs promoted tumorigenesis; the mutant PPP2R1A proteins were defective in binding to the regulatory and catalytic subunits of PP2A, resulting in a decrease in PP2A activity and thus facilitating tumor progression (4).A previous whole-exome sequencing attempt identified recurrent PPP2R1A mutations in 3 out of 42 patients (7.1%) with ovarian clear cell carcinoma (OCCC) (5). Subsequent studies confirmed this finding and also revealed frequent PPP2R1A mutations in patients with ovarian endometrioid carcinoma (6-8). Additionally, a high frequency of PPP2R1A mutations was also identified in several subtypes of endometrial carcinoma, with the highest frequency demonstrated in the serous subtype (6-9). Furthermore, previous studies revealed that PPP2R1A mutations were present ...

A novel somatic MAPK1 mutation in primary ovarian mixed germ cell tumors

“…In addition, no mutations were detected in the remaining samples (Table I Association of MAPK1 mutation with other genetic alterations in ovarian mixed germ cell tumor. We screened our samples for the presence of PPP2R1A, RNF43, POLE1, DICER1, CTCF, RPL22, DNMT3A, TRRAP, IDH1 and IDH2 mutations in our prior (15)(16)(17)(18) and the present study. Nevertheless, no mutation was detected in these genes.…”

“…previously (15)(16)(17). A total of 263 ovarian carcinomas were screened for the potential mutations in the MAPK1 p.E322 and paralogous MAPK3 p.E339 residues (Table I and Fig.…”

“…Each sample was reviewed by two experienced pathologists, all of the recruited samples contained >70% cancerous cells and did not undergo chemotherapy and/or radiotherapy. Among these patients, 251 patients were described previously (15)(16)(17)(18) and the additional 12 patients diagnosed with ovarian mixed germ cell tumor were newly recruited (Table I). In addition, among these cases, 238 paired adjacent non-cancerous samples were also taken from archival blocks of these oophorectomy samples where no cancerous cells were identified by hematoxylin-eosin staining.…”

“…PPP2R1A, RNF43, POLE1, DICER1, CTCF, RPL22, DNMT3A, TRRAP, IDH1 and IDH2 hotspot mutation analyses. The mutational status of several potential ovarian cancer-related genes were analyzed in our samples previously (15)(16)(17)(18) and here (ovarian mixed germ cell tumor, n=12), including PPP2R1A, RNF43, POLE1, DICER1, CTCF, RPL22, DNMT3A, TRRAP, IDH1 and IDH2, the PCR and DNA sequencing reactions were performed as previously described (15)(16)(17)(18).…”

“…In the present study, we analyzed a cohort of 263 Chinese ovarian cancer samples with distinct subtypes for the presence of MAPK1 and MAPK3 mutations. Furthermore, the potential hotspot mutations in several newly-identified cancer-related genes were also analyzed in our samples previously and here, including PPP2R1A, RNF43, POLE1, DICER1, CTCF, RPL22, DNMT3A, TRRAP, IDH1 and IDH2 (15)(16)(17)(18), with the aim of exploring the possibility that these mutations would play synergistic role with MAPK1 mutation in the development of this malignancy.…”