The status of p53 and the
phosphatidylinositol 3-kinase-AKT (PI3K-AKT) signaling pathway was investigated in 132
endometrial carcinomas, including endometrioid
endometrial carcinomas, non-endometrioid
endometrial carcinomas, and mixed
endometrioid adenocarcinomas-non-
endometrioid adenocarcinomas. Results were compared with the clinicopathologic parameters associated with prognosis, patients' follow-up, and other genetic alterations found frequently in these
tumors. Molecular genetic differences between low-grade and high-grade
endometrioid adenocarcinomas were encountered; ie, PIK3CA mutations were detected in 26 and 34% of cases, respectively. We found p53 alterations in only 17% of high-grade
endometrioid adenocarcinomas. In contrast, non-
endometrioid adenocarcinomas had a higher frequency of p53 alterations (54%), PIK3CA
mRNA overexpression (45%), and exon 20 PIK3CA mutations (21%). In the mixed
endometrioid adenocarcinomas-non-
endometrioid adenocarcinomas, the most frequent alterations were p53 (50%) and PIK3CA (44%) mutations, followed by PTEN mutations (38%). In some cases, p53 and PIK3CA alterations coexisted, but they rarely coexisted with the PTEN mutations. Our findings suggest that the PIK3CA mutations are frequent events in
endometrial carcinomas of any histological type. However, location of the PIK3CA mutations, either in exon 9 or exon 20, varies significantly according to the histologic grade and type of
carcinoma.
Carcinomas with exon 20 PIK3CA mutations or PIK3CA
mRNA overexpression were often high-grade
carcinomas associated with myometrial invasion; in contrast,
tumors that carried exon 9 mutations were more likely to be low-grade
carcinomas. The Kaplan-Meier analysis suggested that p53 alterations (strong immunoexpression or mutations) conferred a worse prognosis (P=0.000). Although alterations in the PI3K-AKT signaling pathway alone did not influence overall survival, patients with deregulated PI3K-AKT pathway (PIK3CA and/or PTEN alterations) and p53 alterations had shorter survival (P=0.000) than patients with only p53 alterations. Such a relationship was lost when we considered exon 9 PIK3CA mutations. Our results contribute to further characterize the molecular genetic model for endometrial
carcinogenesis.