p85α, the regulatory subunit of PI3K, is somatically mutated at a high frequency in primary endometrial cancer

Monday, October 24, 2011 — Poster Session I
Noon – 2:00 p.m.	Natcher Conference Center	NHGRI	CANCER-25

* FARE Award Winner

Authors

• ME Urick
• ML Rudd
• AK Godwin
• D Sjroi
• M Merino
• DW Bell

Abstract

New therapeutic options are needed for patients with endometrial cancer. The phosphatidylinositol 3-kinase (PI3K) pathway is an important therapeutic target. PI3K is made up of a p85α regulatory subunit (encoded by the gene PIK3R1), and a p110α catalytic subunit (encoded by PIK3CA). The p85α subunit stabilizes and inhibits the p110α subunit. The purpose of this study was to determine the frequency and relevance of PIK3R1 mutations in endometrial tumors. All coding exons of PIK3R1 were sequenced from 108 primary endometrial tumors and matched normal samples. Wild-type p85α, mutant p85α, or vector controls were over-expressed in U2OS cells and the effects of mutations on binding to p110α and phosphorylation of AKT and S6 proteins were determined. We provided the first report that PIK3R1 is somatically mutated at a high frequency in endometrial tumors in a nonrandom pattern that includes four recurrent mutations and nine overlapping in-frame deletions. Of seven p85α mutants studied, five were able to bind p110α and resulted in increased phosphorylation of AKT and S6. The two mutations studied that did not bind p110α were truncating mutations that co-occur with p110α mutations. In conclusion, we identified a new cohort of endometrial cancer patients that might respond to PI3K-targeted therapies.

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