PIK3CA mutations and amplification in endometrioid endometrial carcinomas: relation to other genetic defects and clinicopathologic status of the tumors.

Alterations of the PIK3CA gene occur in endometrial carcinomas, but their role in the carcinogenesis of those malignancies is still poorly understood. In this study, PIK3CA mutations and amplification in 196 endometrioid endometrial carcinomas and 20 endometrial hyperplasias were assessed by single-strand conformation polymorphism (PCR-SSCP), sequencing, and quantitative polymerase chain reaction. Results were correlated with mutations in the PTEN, KRAS, and CTNNB1 genes and with the clinicopathologic parameters of the tumors. PIK3CA mutations were found in 39 (20%) carcinomas. Six new mutations were identified. No PIK3CA mutations were found in endometrial hyperplasias. PIK3CA amplification was observed in 24 (12.2%) carcinomas and in 2 (10%) hyperplasias. The PIK3CA mutations and amplifications (with the exception of 6 cases) occurred independently. PIK3CA mutations were significantly associated with PTEN mutations (P = .0414) and tended to be associated with CTNNB1 (P = .0833), but not with KRAS mutations. Conversely, the PIK3CA amplifications significantly negatively correlated with PTEN mutations (P = .0038) and did not coexist with CTNNB1 and KRAS mutations. The PIK3CA mutations were significantly associated with poorly differentiated tumors (P = .0423). Interestingly, PIK3CA amplifications, but not mutations, were strongly associated with older age (≥63 years, P = .0018). Our data show that mutations and amplification of PIK3CA are significant genetic alterations in endometrioid endometrial carcinomas associated with adverse clinicopathologic parameters (grade and stage). These data also demonstrate that PIK3CA mutations cooperate with PTEN mutations, suggesting an additive effect to PTEN, whereas PIK3CA amplification can, as an isolated event, enable the development of those tumors. Moreover, for the first time, a possible role of PIK3CA amplification in initiation and progression of endometrial carcinomas in older women is suggested, but this preliminary suggestion requires further research.

TP53 mutations in endometrial cancers: relation to PTEN gene defects.

OBJECTIVE: The PTEN and TP53 genes participate in the carcinogenesis of many malignancies, but the role of both genes in endometrial carcinogenesis is not fully elucidated. The aim of the study was to determine the quality and the frequency of incidence of TP53 and PTEN gene mutations and to assess their coexistence in endometrial cancers. Besides that, the correlation was studied between the detected defects and clinicohistopathological characteristics of the studied endometrial cancers. METHODS: The study material included DNA isolated from 81 endometrial cancers. The incidence of TP53 and PTEN gene mutations was assessed using polymerase chain reaction-single-strand conformation polymorphism and sequencing techniques. The statistical analysis of the results was performed using [chi]2 test. RESULTS: In 64.2% of the 81 endometrial cancers, mutations occurred in TP53 and/or PTEN genes: in 16.1%, mutations occurred only in TP53; in 33.3%, only in PTEN gene; and in 14.8%, in both TP53 and PTEN genes. In 35.8% of cases, no mutations were found in these genes. No statistically significant relationship was found between the incidence of mutations in TP53 gene and that in PTEN gene (P = 0.986). The incidence of mutations in PTEN gene was higher in medium and poorly differentiated endometrial cancers than in well-differentiated ones and was statistically significant (G2 + G3 vs G1; P = 0.049). Besides that, mutations in PTEN gene occurred significantly more frequently in patients younger than 55 years than in older women (> or =55 years; P = 0.027). No similar differences were found in TP53 gene. CONCLUSIONS: The results of the study demonstrate that TP53 gene mutations occur in some of endometrioid endometrial cancers in the presence of PTEN gene mutations, suggesting that both these genes participate in the development of these tumors.

Molecular genetic defects in endometrial carcinomas: microsatellite instability, PTEN and beta-catenin (CTNNB1) genes mutations.

PURPOSE: The present study aims to assess the incidence of microsatellite instability (MSI) and mutations in the PTEN and beta-catenin (CTNNB1) genes in endometrial carcinomas and to analyze the detected defects in these factors in relation to each other and to the clinico-pathological features of tumors. MATERIALS AND METHODS: In a series of 56 endometrioid endometrial carcinomas, the status of MSI was determined using nine polymorphic markers, and mutations in all exons of the PTEN gene and in exon 3 of the CTNNB1 gene were evaluated by SSCP and sequencing methods. RESULTS: Microsatellite instability was found in 18 carcinomas (32.1%, MSI+); the remaining 38 tumors were microsatellite stable (MSI-). In 15 cases (26.8%), a loss of heterozygosity (LOH) at the studied microsatellite markers also occurred. In 29 carcinomas (51.8%), mutations were found in the PTEN gene and in nine tumors (16.1%) in the CTNNB1 gene. PTEN mutations occurred significantly more frequently in MSI+ than in MSI- tumors (77.8 vs. 39.5%, p = 0.007), but, except for one, none of them was attributable to MSI. In contrast, incidence of CTNNB1 mutations in MSI+ and MSI- tumors no significantly differed between themselves (16.7 vs. 15.8%, p = 0.760). Interestingly, mutations in the CTNNB1 gene most frequently coexisted with mutations in the PTEN gene (7/9, 77.8%). However, this finding requires future verification on a larger group of cases. The incidence of MSI and PTEN, but not CTNNB1 mutations, was significantly more common in poorly, than in well-to-moderately, differentiated tumors (G3 vs. G1 + G2; p = 0.042, 0.039 and 0.958, respectively). CONCLUSION: We conclude that most frequently occurring mutations in the PTEN gene may be a key event for the tumorigenesis of endometrioid endometrial carcinomas, while coexistence or absence of microsatellite instability or mutations in the CTNNB1 gene may reflect the heterogeneity of molecular mechanisms contributing to the development of these tumors.

Bicornuate rudimentary uterine horns with functioning endometrium and complete cervical-vaginal agenesis coexisting with ovarian endometriosis: a case report.

OBJECTIVE: To report a patient with bicornuate rudimentary uterine horns with functioning endometrium and complete cervical-vaginal agenesis coexisting with ovarian endometriosis. DESIGN: Case report. SETTING: University hospital. PATIENT(S): A 37-year-old woman with an extremely rare müllerian anomaly of the uterus and vagina coexisting with ovarian endometriosis. INTERVENTION(S): Resection of the rudimentary uterine horns with bilateral salpingo-oophorectomy. MAIN OUTCOME MEASURE(S): Relief from pelvic pain after the operative procedure. RESULT(S): The definite diagnosis and removal of the müllerian anomaly and endometriosis foci. CONCLUSION(S): Cyclic pelvic pain since the age of 14 was due to cryptomenorrhoea in the presence of the bicornuate rudimentary uterine horns with functioning endometrium and cervical-vaginal agenesis. Ovarian endometriosis developed as a result. In such cases, invasive procedures, such as laparoscopy or laparotomy, should be considered to establish the diagnosis. Removing the functioning rudimentary uterine horns just after menarche should prevent the development of endometriosis and hematometra.