Characterization of the 19q12 amplification including CCNE1 and URI in different epithelial ovarian cancer subtypes

Noske, Aurelia; Henricksen, Leigh A.; LaFleur, Bonnie; Zimmermann, Anne-Katrin; Tubbs, Alisa; Singh, Shalini; Storz, Martina; Fink, Daniel; Moch, Holger

doi:10.1016/j.yexmp.2014.12.004

Cited by 21 publications

(28 citation statements)

References 22 publications

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“…Assay interpretation was possible for 270 tissue samples and was performed by a board certified pathologist (A.N.). 19q12 enumeration and chromosome 19 signals were manually completed for 50 tumour nuclei/sample with amplification defined as 19q12/chr19 ratio ≥2.0 [7, 15]. Using this cut-off, copy number alterations were found in 28/270 carcinomas (10.4%).…”

Section: Resultsmentioning

confidence: 99%

“…URI expression was exclusively detected in cytoplasm. For statistics, we categorised the expression as recently described [7]. Moderate and strong cytoplasmic staining (defined as URI-positive) was observed in 12.5% of the carcinomas (52/416) but neither associated with pathological features (Table 2, Figure 1D) nor overall survival (log-rank test, p = 0.68).…”

Section: Resultsmentioning

confidence: 99%

“…Of note, only high-grade EC (4/7) with low level 19q12 amplification by ISH showed CN gain by OncoScan, suggesting ISH may have lower sensitivity for CN gain detection, at least under certain conditions. The evaluation and stratification of 19q12 ISH was performed according to our recent study based on previously published recommendations [4, 7]. Alternatively, OncoScan technology allows for more detailed resolution and subdivision and thus may be superior for low CN gain.…”

Section: Discussionmentioning

confidence: 99%

“…However, the 19q12 amplicon comprises several genes along with CCNE1 , including URI (C19Orf2, RPB5-mediating protein), C19Orf12, POP4 and PLEKHF1 . We and others recently observed URI amplification in carcinomas of the ovary [5–7] and endometrium [6]. The URI protein belongs to the prefoldin family of molecular chaperones involved in translational control-related pathways [8].…”

Section: Introductionmentioning

confidence: 99%

“…We evaluated the prevalence and degree of 19q12 (including CCNE1 and URI ) amplification in a large group of archived EC samples using a recently established chromogenic in situ hybridisation (ISH) assay for automated 19q12 detection with immunohistochemical Cyclin E1 and URI protein expression [7]. To validate the 19q12 ISH data, we analysed a subset of samples for CN changes using the Affymetrix OncoScan assay.…”

Section: Introductionmentioning

confidence: 99%

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Detection ofCCNE1/URI(19q12) amplification byin situhybridisation is common in high grade and type II endometrial cancer

et al. 2016

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One TCGA subgroup of endometrial cancer (EC) is characterised by extensive genomic DNA copy number alterations. CCNE1 located at 19q12 is frequently amplified in EC and a target for anti-cancer therapy. The relevance of URI, also located at 19q12, is unknown. To evaluate the prevalence of 19q12 (CCNE1/URI) in EC, we investigated different histologic types by in situ hybridisation (ISH) and copy number assay. We applied a previously established 19q12 ISH for the detection of CCNE1/URI copy numbers in EC (n = 270) using conventional bright field microscopy. In a subset (n = 21), 19q12 amplification status was validated by OncoScan assay. Manual ISH was controlled by a recently developed computational ISHProfiler algorithm. Associations of 19q12 status with Cyclin E1, URI and p53 expression, and clinico-pathological parameters were tested.Amplification of 19q12 (CCNE1/URI) was found in 10.4% (28/270) and was significantly associated with type II EC (high grade and non-endometrioid; p < 0.0001), advanced FIGO stage (p = 0.001), high Cyclin E1 expression (p = 0.008) and aberrant p53 expression (p = 0.04). 19q12 ISH data were confirmed by OncoScan and computational ISHProfiler techniques. The 19q12 in situ hybridisation is a feasible and robust biomarker assay in molecular pathology. Amplification of CCNE1/URI predominantly occurred in type II endometrial cancer. Prospective clinical trials are warranted to assess the utility of combined 19q12 amplification and Cyclin E1/URI protein expression analysis for the prediction of therapeutic response to chemotherapy and/or cyclin-dependent kinase inhibitors in patients with endometrial cancer.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Detection ofCCNE1/URI(19q12) amplification byin situhybridisation is common in high grade and type II endometrial cancer

et al. 2016

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Combined CCNE1 high‐level amplification and overexpression is associated with unfavourable outcome in tubo‐ovarian high‐grade serous carcinoma

Chan

Enwere

McIntyre

et al. 2020

The Journal of Pathology CR

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CCNE1 amplification is a recurrent alteration associated with unfavourable outcome in tubo-ovarian highgrade 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 cutoff 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 cutoff 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.

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Histo‐genomic stratification reveals the frequent amplification/overexpression of CCNE1 and BRD4 genes in non‐BRCAness high grade ovarian carcinoma

Goundiam

Gestraud

Popova

et al. 2015

Intl Journal of Cancer

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The treatment of epithelial ovarian cancer (EOC) is narrowly focused despite the heterogeneity of this disease in which outcomes remain poor. To stratify EOC patients for targeted therapy, we developed an approach integrating expression and genomic analyses including the BRCAness status. Gene expression and genomic profiling were used to identify genes recurrently (>5%) amplified and overexpressed in 105 EOC. The LST (Large-scale State Transition) genomic signature of BRCAness was applied to define molecular subgroups of EOC. Amplified/overexpressed genes clustered mainly in 3q, 8q, 19p and 19q. These changes were generally found mutually exclusive. In the 85 patients for which the genomic signature could be determined, genomic BRCAness was found in 52 cases (61.1%) and non-BRCAness in 33 (38.8%). A striking mutual exclusivity was observed between BRCAness and amplification/overexpression data. Whereas 3q and 8q alterations were preferentially observed in BRCAness EOC, most alterations on chromosome 19 were in non-BRCAness cases. CCNE1 (19q12) and BRD4 (19p13.1) amplification/overexpression was found in 19/33 (57.5%) of non-BRCAness cases. Such disequilibrium was also found in the TCGA EOC data set used for validation. Potential target genes are frequently amplified/overexpressed in non-BRCAness EOC. We report that BRD4, already identified as a target in several tumor models, is a new potential target in high grade non-BRCAness ovarian carcinoma.Epithelial ovarian cancer (EOC) is the seventh most common cause of cancer related death in women. 1 This high mortality rate is a result of delayed diagnosis and limited therapeutic options. The reference treatment of EOC is an association of surgical cytoreduction and platinum-based chemotherapy. About 80% of tumors respond to the first line of treatment 2 but a relapse develops in most cases and there is no curative treatment for recurrent diseases.EOC spans many diseases that differ in their histology, primary anatomical location and molecular features. Histologically, serous (40%), endometrioid (24%) mucinous (6%) and clear cells (26%) are the most frequent. 3 The classical three-tier histological grading system was recently modified as a binary system for serous carcinoma. 4 Anatomically, though a subset of endometrioid and clear cell carcinoma are known to develop from pelvic endometriosis, the extensive study of prophylactic oophoro-salpingectomy specimens revealed that a notable proportion of high grade serous ovarian cancers are actually derived from the distal fallopian tube. 5 Bio-pathological studies have shown that histological subtypes progress through distinct biological pathways. Two

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Characterization of the 19q12 amplification including CCNE1 and URI in different epithelial ovarian cancer subtypes

Cited by 21 publications

References 22 publications

Detection ofCCNE1/URI(19q12) amplification byin situhybridisation is common in high grade and type II endometrial cancer

Detection ofCCNE1/URI(19q12) amplification byin situhybridisation is common in high grade and type II endometrial cancer

Combined CCNE1 high‐level amplification and overexpression is associated with unfavourable outcome in tubo‐ovarian high‐grade serous carcinoma

Histo‐genomic stratification reveals the frequent amplification/overexpression of CCNE1 and BRD4 genes in non‐BRCAness high grade ovarian carcinoma

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