PIK3CA and PTEN Mutations in Uterine Endometrioid Carcinoma and Complex Atypical Hyperplasia

Abstract

Purpose: The tumor suppressor PTEN gene and the PIK3CA oncogene are frequently mutated in uterine endometrioid carcinoma (UEC). PTEN mutations are also common in complex atypical hyperplasia (CAH), the precursor lesion of UEC. The status of PIK3CA has not yet been explored in CAH. In this study, we evaluated both CAH and UEC for PTEN and PIK3CA mutations. Experimental Design: Neoplastic tissue was microdissected, and DNA was extracted from 29 cases of CAH. DNA was available from 44 UEC cases previously characterized for PTEN mutations. Direct DNA sequencing of exons 9 and 20 of the PIK3CA gene was done on all 73 cases. In addition, CAH cases were analyzed for PTEN mutations. Statistical analyses were done using the Fisher's exact test. Results: Two (7%) of 29 CAH and 17 (39%) of 44 UEC cases contained a PIK3CA mutation (P = 0.003). Fourteen (48%) of 29 CAH cases had a PTEN mutation, but none contained both a PTEN and PIK3CA mutation. Twenty-five (57%) of 44 UEC cases had a PTEN mutation, and 12 (48 %) of these 25 cases also contained a PIK3CA mutation. Coexistent PIK3CA and PTEN mutations were significantly correlated with UEC compared with CAH (P = 0.002), but the association in UEC did not reach statistical significance (P = 0.21). Conclusions: PIK3CA is the most commonly mutated oncogene in UEC; however, mutations are uncommon in CAH. Thus, mutations in PIK3CA, unlike PTEN mutations, are associated with invasion.These findings suggest that mutations in PIK3CA may serve as a marker of invasion with potential clinical use. Furthermore, PIK3CA and PTEN mutations may play distinct roles in endometrial tumorigenesis.Within the last 10 years, our knowledge of the molecular genetics of endometrial cancer has expanded with the discovery of mutations in genes, such as PTEN, K-RAS, CTNNB1, and TP53. These discoveries have led to a better understanding of the pathogenesis of endometrial cancer and its distinct histologic subtypes, broadly categorized as type I and II cancers, which are thought to arise via different pathogenetic pathways. Uterine endometrioid carcinoma (UEC) is the most common histologic subtype, representing >85% of cases. Not only is PTEN the most commonly mutated gene in UEC, the mutations also occur early in its pathogenesis as they are present at approximately the same frequency in complex atypical hyperplasias (CAH), the precursor lesion of UEC (1, 2).Recently, mutations of a novel oncogene (PIK3CA) were discovered in multiple human epithelial cancers, including UEC (3, 4). PIK3CA encodes the catalytic p110-a subunit of phosphatidylinositol 3-kinase (PI3K), a lipid kinase that generates phosphatidyl inositol-3,4,5-triphosphate by phosphorylating phosphatidyl inositol-3,4-diphosphate. This in turn activates the AKT/mammalian target of rapamycin oncogenic pathway, directly opposing the actions of the lipid phosphatase PTEN (5). It is unclear what role mutations in PIK3CA play during endometrial tumorigenesis and what, if any, additional role they confer over PTEN mutations. Recent literatur...

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

“…31 In a comparative study of 44 endometrioid adenocarcinomas and 29 precursor lesions (complex atypical hyperplasias), PIK3CA mutations were identified in 39% of the former but only 7% of the latter, suggesting that such mutations represent a late event in endometrial carcinogenesis and are associated with invasion. 28 However, in contrast to colorectal and breast carcinomas, a correlation between PIK3CA mutations and tumor grade or clinicopathological stage was neither encountered in this 28 nor in a previous mutational study of 66 endometrial carcinomas. 25 Conversely, we found that tumor grade varied significantly according to the distribution of PIK3CA mutations between exons 9 and 20 (P ¼ 0.033).…”

“…25,27,28 Mutations were found predominantly in exon 20 in two studies, 25,27 and evenly distributed between exons 9 and 20 in a third. 28 In our series, we encountered 35 mutations in 32 (29%) tumors, and almost all (91%) were pure endometrioid adenocarcinomas. Microdissection of the different histologic components was performed in the three mixed carcinomas with PIK3CA mutations, which were found in the endometrioid component in all three cases.…”

“…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.…”

“…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.…”