PPP2R1A mutation status as a predictive and prognostic factor in molecularly characterized endometrial carcinoma: A cohort study

To evaluate associations of mutations in PPP2R1A, encoding the Aα subunit of protein phosphatase 2A (PP2A), with molecular sub-groups, clinicopathologic factors, predictive/prognostic biomarkers, and survival in endometrial carcinoma. This retrospective study used sequencing, immunohistochemistry, and dual-color chromogenic in situ hybridization to assess PPP2R1A mutations, molecular sub-groups, and PD-L1, human epidermal growth factor receptor 2 (HER2), estrogen receptor, and L1 cell adhesion molecule status. A total of 436 patients were analyzed (median follow-up: 48 months). A total of 37 tumors (8.4%) harbored PPP2R1A mutations. They were associated with stage II to IV disease (p = .010), molecular sub-group (p < .001), and histotype (p < .001). Among PPP2R1A-mutated tumors, 54.1% (n = 20) were p53-abnormal, and 40.5% (n = 15) were non-endometrioid. Mismatch repair, PD-L1, HER2, and L1 cell adhesion molecule status did not differ between the PPP2R1A-mutated and wild-type groups. Estrogen receptor expression was more common in wild-type tumors (p = .003). Of the 33 PPP2R1A-mutated tumors with known mismatch repair and PD-L1 immunohistochemistry and HER2 amplification status, 51.5% (n = 17) were negative for all signatures. When estrogen receptor was included as a predictive parameter, 13.3% (4 of 30) were negative for all 4. PPP2R1A mutations were associated with poorer progression-free (p = .001) and disease-specific survival (p < .001) but not overall survival (p = .058). After adjusting for molecular sub-groups and clinicopathological risk groups, PPP2R1A mutations were not associated with outcomes. Among PPP2R1A-mutated tumors, p53 abnormalities were associated with poorer outcomes than the p53 wild-type phenotype. Although PPP2R1A mutations are linked to aggressive clinicopathological features, they do not independently predict endometrial carcinoma survival. Given the absence of non-hormonal targets in half of PPP2R1A-mutated carcinomas, PP2A-targeted therapies are needed. Survival analysis suggests that the role of p53 in progression likely extends beyond its interaction with PP2A.