PIK3R1 (p85α) Is Somatically Mutated at High Frequency in Primary Endometrial Cancer

Phosphoinositide 3-kinase (PI3K) is an important therapeutic target. Mutations in PIK3CA, which encodes p110 alpha, the catalytic subunit of PI3K, occur in endometrioid endometrial cancers (EEC) and nonendometrioid endometrial cancers (NEEC). The goal of this study was to determine whether PIK3R1, which encodes p85 alpha, the inhibitory subunit of PI3K, is mutated in endometrial carcinoma. We carried out exonic sequencing of PIK3R1 from 42 EECs and 66 NEECs. The pattern of PIK3R1 mutations was compared with the patterns of PIK3CA, PTEN, and KRAS mutations. The biochemical effect of seven PIK3R1 mutations was examined by stable expression in U2OS cells, followed by coimmunoprecipitation analysis of p110 alpha, and Western blotting of phospho-AKT(Ser473) (p-AKT(Ser473)). We found that PIK3R1 was somatically mutated in 43% of EECs and 12% of NEECs. The majority of mutations (93.3%) were localized to the p85 alpha-nSH2 and -iSH2 domains. Several mutations were recurrent. PIK3R1 mutations were significantly (P = 0.0015) more frequent in PIK3CA-wild type EECs (70%) than in PIK3CA mutant EECs (18%). Introduction of wild-type p85 alpha into U2OS cells reduced the level of p-AKT(Ser473) compared with the vector control. Five p85 alpha mutants, p85 alpha delH450-E451, p85 alpha delK459, p85 alpha delY463-L466, p85 alpha delR574-T576, and the p85 alpha N564D positive control, were shown to bind p110 alpha and led to increased levels of p-AKT(Ser473). The p85 alpha R348X and p85 alpha K511VfsX2 mutants did not bind p110 alpha and showed no appreciable change in p-AKT(Ser473) levels. In conclusion, our study has revealed a new mode of PI3K alteration in primary endometrial tumors and warrants future studies to determine whether PIK3R1 mutations correlate with clinical outcome to targeted therapies directed against the PI3K pathway in EEC and NEEC. Cancer Res; 71(12); 4061-7. (C)2011 AACR.