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Loss of PTEN expression is an independent predictor of favourable survival in endometrial carcinomas.

ABSTRACT: We and others previously reported the prognostic significance of PTEN mutational status on favourable survival in endometrial carcinomas. Here, we demonstrate that loss of PTEN expression in immunohistochemistry is an independent prognostic marker for favourable survival in endometrial carcinomas.We conducted immunohistochemical analyses of PTEN, PIK3CA, phosphorylated Akt (p-Akt), and p27 in primary endometrial carcinomas from 221 patients. Mutation of PTEN was analysed further.Expression of PTEN was lost in 56 patients (25%), and PIK3CA was overexpressed in 159 patients (72%). Overexpression of PIK3CA was associated with p-Akt overexpression (P<0.001), which was in turn associated with loss of nuclear p27 expression (P=0.028). Loss of PTEN expression was found to be associated with endometrioid histology (P=0.03), and was inversely associated with the presence of lymphovascular space invasion (P=0.03). Univariate and multivariate survival analyses revealed that factors of PTEN loss, age <70, histological grade 1, early International Federation of Gynecology and Obstetrics (FIGO) stage, and absence of lymphovascular invasion were independent prognostic indicators for better overall survival (P=0.03, 0.04, 0.01, <0.001, and 0.03, respectively). The subset analysis showed a stronger tendency of PTEN loss towards favourable survival in advanced-stage (III and IV) disease than in early-stage (I and II) disease (P=0.05 vs 0.14). Moreover, our mutational analysis demonstrated that PTEN expression loss was associated with PTEN-truncating mutations (P=0.03).The current observations further support the prognostic significance of PTEN aberration on favourable outcome in endometrial carcinomas, providing useful implications for the individualised management of the disease.

SUBMITTER: Akiyama-Abe A

PROVIDER: S-EPMC3776978 | biostudies-other | 2013 Sep

REPOSITORIES: biostudies-other

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Project description:AimsDedifferentiated endometrial carcinomas (DDECs)/undifferentiated endometrial carcinomas (UECs) are aggressive endometrial cancers with frequent genomic inactivation of core components of switch/sucrose non-fermentable (SWI/SNF) complex proteins. Claudin-4, an epithelial intercellular tight junction protein, was recently found to be expressed in SWI/SNF-deficient undifferentiated carcinomas but not in SWI/SNF-deficient sarcomas. The aim of this study was to examine claudin-4 expression in UECs/DDECs and other high-grade uterine carcinomas.Methods and resultsWe examined claudin-4 expression by immunohistochemistry (clone 3E2C1) on tissue microarrays that contained 44 UECs/DDECs (24 SWI/SNF-deficient), 50 carcinosarcomas, 164 grade 3 endometrioid carcinomas, 57 serous carcinomas, and 20 clear cell carcinomas. Tumours with <5% claudin-4 expression were considered to be negative. Nearly all SWI/SNF-deficient, and most SWI/SNF-proficient, UECs/DDECs showed a complete absence of claudin-4 expression in the undifferentiated component, whereas the differentiated component in DDECs showed consistent and diffuse claudin-4 expression. Only one SWI/SNF-deficient DDEC showed focal expression of claudin-4 in the undifferentiated component, as compared with diffuse expression in the corresponding differentiated component. Claudin-4 expression was consistently absent in the sarcomatous component of carcinosarcoma, and it was absent in 24% of grade 3 endometrioid carcinomas and serous carcinomas.ConclusionClaudin-4 expression can be absent or very focal in a subset of high-grade endometrial carcinomas, and is almost always absent in the undifferentiated components of SWI/SNF-deficient UECs/DDECs, despite the apparent epithelial origin in the case of DDECs. Therefore, claudin-4 expression cannot be used to infer mesenchymal or epithelial tumour origin in the endometrium. The consistent loss or down-regulation of claudin-4, a tight junction protein, in SWI/SNF-deficient UECs/DDECs further supports the undifferentiated nature of these tumours.

Project description:BackgroundAdherence to National Comprehensive Cancer Network guidelines have been adopted as the standard of care for various cancers and have been cited to have survival benefits. Few studies have examined the association of adherent treatment and endometrial cancer survival among various racial/ethnic groups and socioeconomic statuses.MethodsBetween January 1, 2006 and December 31, 2015, 83,673 women diagnosed with endometrial carcinomas were identified from the Surveillance, Epidemiology, and End Results database. Descriptive statistics of demographic and clinical characteristics were performed. Cox-proportional hazards models were used to examine the effect on cause-specific survival for adherence to guidelines across racial/ethnic and socioeconomic groups.ResultsWithin our sample, 59.5% were treated according to guidelines. Nonadherence to treatment guidelines was significantly associated with decreased survival compared with adherent care (adjusted hazard ratio [HR], 1.59; 95% CI, 1.52-1.67). Being of Black (adjusted HR, 1.41; 95% CI, 1.32-1.51) or Native Hawaiian/Pacific Islander (adjusted HR, 1.44; 95% CI, 1.19-1.73) race/ethnicity compared with White women was significantly associated with worse survival. Being of Asian race/ethnicity (adjusted HR, 0.86, 95% CI, 0.78-0.94) was significantly associated with improved survival compared with White women. Lower neighborhood socioeconomic status was associated with a negative effect on survival relative to women in the highest socioeconomic status category.ConclusionsFindings from this study suggest treatment adherence is an independent predictor of improved survival; however, improved survival was not observed equally among all racial/ethnic and socioeconomic status groups.Lay summaryThe National Comprehensive Cancer Network (NCCN) has developed guidelines for physicians to follow in treating various cancers. Within this study of 83,673 women with endometrial cancer, 59.5% of women were treated according to the NCCN guidelines. The findings suggest following NCCN guidelines for treatment of endometrial cancer improves survival. Black or Native Hawaiian/Pacific Islander race and lower neighborhood socioeconomic status has worse survival rates compared with other groups, indicating the importance of exploring other factors that may shape treatment across racial/ethnic and socioeconomic status groups.

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Loss of PTEN expression is an independent predictor of favourable survival in endometrial carcinomas.

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