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CCNE1 expression in high grade serous carcinoma does not correlate with chemoresistance.

ABSTRACT: Delayed diagnosis of ovarian cancer, as well as high recurrence rates and lack of personalized therapy options, are among the causes for poor survival figures. Much effort is made towards developing new therapeutic possibilities, however predictive biomarkers are still unavailable. CCNE1 amplification, occurring in ?20% of the high grade serous ovarian tumors, was previously proposed as a marker for platinum resistance and poor prognosis as well as for CDK2 inhibition. The current study aimed to examine the role of CCNE1 positive-immunostain as a predictor of first-line taxane-platinum chemoresistance. We evaluated matched pre- vs. post-neoadjuvant chemotherapy tumor samples and correlated the degree of pathological response to treatment with CCNE1 expression levels. Our results indicate that CCNE1 immunohistochemistry does not predict taxane-platinum chemoresistance in ovarian cancer patients. Further research is required in order to enable personalized adjuvant treatment, in cases where poor pathological response is achieved after the neoadjuvant phase.

SUBMITTER: Sapoznik S

PROVIDER: S-EPMC5617501 | biostudies-literature | 2017 Sep

REPOSITORIES: biostudies-literature

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CCNE1 expression in high grade serous carcinoma does not correlate with chemoresistance.

Sapoznik Stav S Aviel-Ronen Sarit S Bahar-Shany Keren K Zadok Oranit O Levanon Keren K

Oncotarget 20170715 37

Delayed diagnosis of ovarian cancer, as well as high recurrence rates and lack of personalized therapy options, are among the causes for poor survival figures. Much effort is made towards developing new therapeutic possibilities, however predictive biomarkers are still unavailable. CCNE1 amplification, occurring in ∼20% of the high grade serous ovarian tumors, was previously proposed as a marker for platinum resistance and poor prognosis as well as for CDK2 inhibition. The current study aimed to ...[more]

PMID: 28977941

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Project description:CCNE1 amplification is a recurrent alteration associated with unfavourable outcome in tubo-ovarian high-grade serous carcinoma (HGSC). We aimed to investigate whether immunohistochemistry (IHC) can be used to identify CCNE1 amplification status and to validate whether CCNE1 high-level amplification and overexpression are prognostic in HGSC. A testing set of 528 HGSC samples stained with two optimised IHC assays (clones EP126 and HE12) was subjected to digital image analysis and visual scoring. DNA and RNA chromogenic in situ hybridisation for CCNE1 were performed. IHC cut-off was determined by receiver operating characteristics (ROC). Survival analyses (endpoint ovarian cancer specific survival) were performed and validated in an independent validation set of 764 HGSC. Finally, combined amplification/expression status was evaluated in cases with complete data (n = 1114). CCNE1 high-level amplification was present in 11.2% of patients in the testing set and 10.2% in the combined cohort. The optimal cut-off for IHC to predict CCNE1 high-level amplification was 60% positive tumour cells with at least 5% strong staining cells (sensitivity 81.6%, specificity 77.4%). CCNE1 high-level amplification and overexpression were associated with survival in the testing and validation set. Combined CCNE1 high-level amplification and overexpression was present in 8.3% of patients, mutually exclusive to germline BRCA1/2 mutation and significantly associated with a higher risk of death in multivariate analysis adjusted for age, stage and cohort (hazard ratio = 1.78, 95 CI% 1.38-2.26, p < 0.0001). CCNE1 high-level amplification combined with overexpression identifies patients with a sufficiently poor prognosis that treatment alternatives are urgently needed. Given that this combination is mutually exclusive to BRCA1/2 germline mutations, a predictive marker for PARP inhibition, CCNE1 high-level amplification combined with overexpression may serve as a negative predictive test for sensitivity to PARP inhibitors.

Project description:High grade serous ovarian carcinoma (HGSC) without identifiable serous tubal intraepithelial carcinoma (STIC) within the fallopian tube (FT) occurs in approximately 50% of patients. The objective of this study was to use a multisite tumor sampling approach to study HGSC with and without STIC. RNAseq analysis of HGSC samples collected from multiple sites e.g. ovary, FT and peritoneum, revealed moderate levels of intrapatient heterogeneity in gene expression that could influence molecular profiles. Mixed-model ANOVA analysis of gene expression in tumor samples from patients with multiple tumor sites (n?=?13) and patients with a single site tumor sample (n?=?11) to compare HGSC-STIC to HGSC-NOSTIC identified neurotensin (NTS) as significantly higher (> two-fold change, False Discovery Rate (FDR)?<?0.10) in HGSC-STIC. This data was validated using publicly available RNA-Seq datasets. Concordance between higher NTS gene expression and NTS peptide levels in HGSC-STIC samples was demonstrated by immunohistochemistry. To determine the role of NTS in HGSC, five ovarian cancer (OvCa) cell lines were screened for expression of NTS and its receptors, NTSR1 and NTSR3. Increased expression of NTS and NSTR1 was observed in several of the OvCa cells, whereas the NTSR3 receptor was lower in all OvCa cells, compared to immortalized FT epithelial cells. Treatment with NTSR1 inhibitor (SR48692) decreased cell proliferation, but increased cell migration in OvCa cells. The effects of SR48692 were receptor mediated, since transient RNAi knockdown of NTSR1 mimicked the migratory effects and knockdown of NTSR3 mimicked the anti-proliferative effects. Further, knockdown of NTSR1 or NTSR3 was associated with acquisition of distinct morphological phenotypes, epithelial or mesenchymal, respectively. Taken together, our results reveal a difference in a biologically active pathway between HGSC with and without STIC. Furthermore, we identify neurotensin signaling as an important pathway involved in cell proliferation and epithelial-mesenchymal transition in HGSC-STIC which warrants further study as a potential therapeutic target. © 2019 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

Dataset Information

CCNE1 expression in high grade serous carcinoma does not correlate with chemoresistance.

Publications

CCNE1 expression in high grade serous carcinoma does not correlate with chemoresistance.

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