High Frequency of PIK3R1 and PIK3R2 Mutations in Endometrial Cancer Elucidates a Novel Mechanism for Regulation of PTEN Protein Stability

We demonstrate that phosphatidylinositol 3-kinase (PI3K) pathway aberrations occur in >80% of endometrioid endometrial cancers, with coordinate mutations of multiple PI3K pathway members being more common than predicted by chance. PIK3R1 (p85 alpha) mutations occur at a higher rate in endometrial cancer than in any other tumor lineage, and PIK3R2 (p85 beta), not previously demonstrated to be a cancer gene, is also frequently mutated. The dominant activation event in the PI3K pathway appears to be PTEN protein loss. However, in tumors with retained PTEN protein, PI3K pathway mutations phenocopy PTEN loss, resulting in pathway activation. KRAS mutations are common in endometrioid tumors activating independent events from PI3K pathway aberrations. Multiple PIK3R1 and PIK3R2 mutations demonstrate gain of function, including disruption of a novel mechanism of pathway regulation wherein p85 alpha dimers bind and stabilize PTEN. Taken together, the PI3K pathway represents a critical driver of endometrial cancer pathogenesis and a novel therapeutic target. SIGNIFICANCE: Our data indicate that the PI3K pathway is targeted in the vast majority of endometrioid endometrial cancers leading to PI3K pathway activation. Frequent oncogenic mutations in PIK3R1 and PIK3R2 provide evidence for their role in endometrial cancer pathophysiology with patient-specific mutations revealing a novel mechanism by which p85 alpha regulates the PI3K pathway through stabilizing PTEN. Cancer Discovery; 1(2); 170-85. (C)2011 AACR.