<i>PIK3CA</i> Amplification Associates with Aggressive Phenotype but Not Markers of AKT-MTOR Signaling in Endometrial Carcinoma.

Abstract

Amplification of <i>PIK3CA</i>, encoding the PI3K catalytic subunit alpha, is common in uterine corpus endometrial carcinoma (UCEC) and linked to an aggressive phenotype. However, it is unclear whether <i>PIK3CA</i> amplification acts via PI3K activation. We investigated the association between <i>PIK3CA</i> amplification, markers of PI3K activity, and prognosis in a large cohort of UCEC specimens. UCECs from 591 clinically annotated patients including 83 tumors with matching metastasis (<i>n</i> = 188) were analyzed by FISH to determine <i>PIK3CA</i> copy-number status. These data were integrated with mRNA and protein expression and clinicopathologic data. Results were verified in The Cancer Genome Atlas dataset. <i>PIK3CA</i> amplifications were associated with disease-specific mortality and with other markers of aggressive disease. <i>PIK3CA</i> amplifications were also associated with other amplifications characteristic of the serous-like somatic copy-number alteration (SCNA)-high subgroup of UCEC. Tumors with <i>PIK3CA</i> amplification also demonstrated an increase in phospho-p70S6K but had decreased levels of activated phospho-AKT1-3 as assessed by Reverse Phase Protein Arrays and an mRNA signature of MTOR inhibition. <i>PIK3CA</i> amplification is a strong prognostic marker and a potential marker for the aggressive SCNA-high subgroup of UCEC. Although <i>PIK3CA</i> amplification associates with some surrogate measures of increased PI3K activity, markers for AKT1-3 and MTOR signaling are decreased, suggesting that this signaling is not a predominant pathway to promote cancer growth of aggressive serous-like UCEC. Moreover, these associations may reflect features of the SCNA-high subgroup of UCEC rather than effects of <i>PIK3CA</i> amplification itself.