High Frequency of Coexistent Mutations of PIK3CA and PTEN Genes in Endometrial Carcinoma

Abstract

The phosphatidylinositol 3V-kinase (PI3K) pathway is activated in many human cancers. In addition to inactivation of the PTEN tumor suppressor gene, mutations or amplifications of the catalytic subunit A of PI3K (PIK3CA) have been reported. However, the coexistence of mutations in these two genes seems exceedingly rare. As PTEN mutations occur at high frequency in endometrial carcinoma, we screened 66 primary endometrial carcinomas for mutations in the helical and catalytic domains of PIK3CA. We identified a total of 24 (36%) mutations in this gene and coexistence of PIK3CA/PTEN mutations at high frequency (26%). PIK3CA mutations were more common in tumors with PTEN mutations (17 of 37, 46%) compared with those without PTEN mutations (7 of 29, 24%). Array comparative genomic hybridization detected 3q24-qter amplification, which covers the PIK3CA gene (3q26.3), in one of nine tumors. Knocking down PTEN expression in the HEC-1B cell line, which possesses both K-Ras and PIK3CA mutations, further enhances phosphorylation of Akt (Ser 473 ), indicating that double mutation of PIK3CA and PTEN has an additive effect on PI3K activation. Our data suggest that the PI3K pathway is extensively activated in endometrial carcinomas, and that combination of PIK3CA/PTEN alterations might play an important role in development of these tumors. (Cancer Res 2005; 65(23): 10669-73)

PIK3CA and PTEN mutations in adenoid cystic carcinoma of the breast metastatic to kidney

“…9 However, recently published studies in endometrial carcinoma demonstrated that coexistent mutations of PIK3CA and PTEN genes are indeed possible. 10 Our case also showed that such combination can also occur in mammary ACC. Furthermore, we showed that reduced expression of PTEN can also occur through increases in promoter methylation.…”

PIK3CA mutations in the kinase domain (exon 20) of uterine endometrial adenocarcinomas are associated with adverse prognostic parameters

“…25,27,28 However, in contrast to other epithelial cancers, such as colorectal 31,36 and breast carcinomas, 37,38 no correlation has been found between the distribution of PIK3CA mutations and grade and stage of disease. Given the recently reported role of PIK3CA mutations in tumor invasion and metastases, 29 we analyzed the PIK3CA status in a large series of endometrial adenocarcinomas and compared the results, between PIK3CA-mutated and PIK3CA-nonmutated groups, with the clinicopathological parameters known to be related to prognosis.…”

“…20,21 The phosphatidylinositol 3 0 -kinase (PI3K)/AKT signaling pathway is frequently activated in multiple human epithelial cancers, including endometrioid adenocarcinomas. [22][23][24][25] In response to cell-surface receptor signals, PI3K phosphorylates phosphatidylinositol 4,5-biphosphate to generate the second messenger phosphatidylinositol 3,4,5-triphosphate. This, in turn, activates the AKT oncogenic pathway, directly counteracting the actions of the lipid phosphatase PTEN.…”

“…A high frequency of mutations of the oncogene PIK3CA, which encodes the p110a catalytic subunit of PI3K, has been recently identified in endometrioid adenocarcinomas. 25,27,28 These mutations are usually of the missense type and clustered in exon 9 (residues E542 and E545 of the helical domain) and exon 20 (residue H1047 of the kinase domain). However, in contrast to other epithelial cancers, no association has been found between the distribution of PIK3CA mutations and the traditional prognostic parameters of endometrioid adenocarcinomas.…”

“…However, in contrast to other epithelial cancers, no association has been found between the distribution of PIK3CA mutations and the traditional prognostic parameters of endometrioid adenocarcinomas. 25,28 Given the reported role of PIK3CA mutations in tumor invasion and metastases, 29 we were interested in determining the clinicopathological impact of PIK3CA mutations in a large series of endometrial adenocarcinomas and their relationship with other genetic alterations also common in these tumors. We found that all carcinomas with PIK3CA mutations exhibited myometrial invasion and, furthermore, histological grade and depth of myometrial invasion varied significantly according to the distribution of mutations between exons 9 and 20.…”