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RNASeq analysis reveals biological processes governing the clinical behaviour of endometrioid and serous endometrial cancers.

ABSTRACT: Endometrial carcinoma comprises a group of tumours with distinct histologic and molecular features and clinical behaviour. Here, we sought to define the biological processes that govern the clinical behaviour of endometrial cancers.Sixteen prototype genes representative of different biological processes that would likely play a role in endometrial and other hormone-driven cancers were defined. RNA-sequencing gene expression data from 323 endometrial cancers from The Cancer Genome Atlas (TCGA) were used to determine the transcription module of each prototype gene. The expression of prototype genes and modules and their association with outcome was assessed in univariate and multivariate survival analyses. The association of MSH6 expression with outcome was validated in an independent cohort of 243 primary endometrial cancers using immunohistochemistry.We observed that the clinical behaviour of endometrial cancers as a group was associated with hormone receptor signalling, PI3K pathway signalling and DNA mismatch repair processes. When analysed separately, in endometrioid carcinomas, hormone receptor, PI3K and DNA mismatch repair modules were significantly associated with outcome in univariate analysis, whereas the clinical behaviour of serous cancers was likely governed by apoptosis and Wnt signalling. Multivariate survival analysis revealed that MSH6 gene expression was associated with outcome of endometrial cancer patients independently from traditional prognostic clinicopathologic parameters, which was confirmed in an independent cohort at the protein level.Endometrioid and serous endometrial cancers are underpinned by distinct molecular pathways. MSH6 expression levels may be associated with outcome in endometrial cancers as a group.

SUBMITTER: Lemetre C

PROVIDER: S-EPMC5099283 | biostudies-literature | 2016 Sep

REPOSITORIES: biostudies-literature

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RNASeq analysis reveals biological processes governing the clinical behaviour of endometrioid and serous endometrial cancers.

Lemetre Christophe C Vieites Begoña B Ng Charlotte K Y CK Piscuoglio Salvatore S Schultheis Anne M AM Marchiò Caterina C Murali Rajmohan R Lopez-García Maria A MA Palacios Jose C JC Jungbluth Achim A AA Terracciano Luigi M LM Reis-Filho Jorge S JS Weigelt Britta B

European journal of cancer (Oxford, England : 1990) 20160714

<h4>Background</h4>Endometrial carcinoma comprises a group of tumours with distinct histologic and molecular features and clinical behaviour. Here, we sought to define the biological processes that govern the clinical behaviour of endometrial cancers.<h4>Methods</h4>Sixteen prototype genes representative of different biological processes that would likely play a role in endometrial and other hormone-driven cancers were defined. RNA-sequencing gene expression data from 323 endometrial cancers fro ...[more]

PMID: 27420608

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Project description:Our aim was to investigate whether molecular classification can be used to refine prognosis in grade 3 endometrial endometrioid carcinomas (EECs). Grade 3 EECs were classified into 4 subgroups: p53 abnormal, based on mutant-like immunostaining (p53abn); MMR deficient, based on loss of mismatch repair protein expression (MMRd); presence of POLE exonuclease domain hotspot mutation (POLE); no specific molecular profile (NSMP), in which none of these aberrations were present. Overall survival (OS) and recurrence-free survival (RFS) rates were compared using the Kaplan-Meier method (Log-rank test) and univariable and multivariable Cox proportional hazard models. In total, 381 patients were included. The median age was 66 years (range, 33 to 96?y). Federation Internationale de Gynecologie et d'Obstetrique stages (2009) were as follows: IA, 171 (44.9%); IB, 120 (31.5%); II, 24 (6.3%); III, 50 (13.1%); IV, 11 (2.9%). There were 49 (12.9%) POLE, 79 (20.7%) p53abn, 115 (30.2%) NSMP, and 138 (36.2%) MMRd tumors. Median follow-up of patients was 6.1 years (range, 0.2 to 17.0?y). Compared to patients with NSMP, patients with POLE mutant grade 3 EEC (OS: hazard ratio [HR], 0.36 [95% confidence interval, 0.18-0.70]; P=0.003; RFS: HR, 0.17 [0.05-0.54]; P=0.003) had a significantly better prognosis; patients with p53abn tumors had a significantly worse RFS (HR, 1.73 [1.09-2.74]; P=0.021); patients with MMRd tumors showed a trend toward better RFS. Estimated 5-year OS rates were as follows: POLE 89%, MMRd 75%, NSMP 69%, p53abn 55% (Log rank P=0.001). Five-year RFS rates were as follows: POLE 96%, MMRd 77%, NSMP 64%, p53abn 47% (P=0.000001), respectively. In a multivariable Cox model that included age and Federation Internationale de Gynecologie et d'Obstetrique stage, POLE and MMRd status remained independent prognostic factors for better RFS; p53 status was an independent prognostic factor for worse RFS. Molecular classification of grade 3 EECs reveals that these tumors are a mixture of molecular subtypes of endometrial carcinoma, rather than a homogeneous group. The addition of molecular markers identifies prognostic subgroups, with potential therapeutic implications.

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RNASeq analysis reveals biological processes governing the clinical behaviour of endometrioid and serous endometrial cancers.

Publications

RNASeq analysis reveals biological processes governing the clinical behaviour of endometrioid and serous endometrial cancers.

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