Abstract GMM-046: CCNE1 AND BRD4 EXPRESSION AND PLATINUM RESISTANCE IN HIGH-GRADE SEROUS OVARIAN CANCERS
Authors: Shariska Petersen, Andrew J. Wilson, Dineo Khabele
Journal: Clinical Cancer Research (2019)

Abstract BACKGROUND: Epithelial ovarian cancer (EOC) is the deadliest gynecologic cancer and the fifth leading cause of cancer deaths among women in the United States. An even poorer prognostic type of EOC is BRCA wild-type CCNE1 (cyclin E) amplified/gain tumors. This subtype of EOC is characterized by unchecked replication, high levels of genomic instability, and replicative stress. CCNE1 amplified EOC is mutually exclusive to BRCA mutated EOC in part because CCNE1 amplified cells require functional BRCA for survival. Bromodomain and extraterminal 4 (BRD4) amplified ovarian cancer is a recently discovered subtype of BRCA wild-type EOC, and is also associated with poor outcomes. OBJECTIVE: To determine if mRNA and immunohistochemical (IHC) profiles of CCNE1 and BRD4 are associated with platinum sensitivity in serous ovarian cancers. METHODS: Copy number analysis data was extracted from The Cancer Genome Atlas (TCGA) for high-grade serous ovarian tumors with BRD4 and CCNE1 (cyclin E) amplification. (www.cbioportal.org). Immunostaining for cyclin E and BRD4 was performed in 130 serous ovarian tumors on a tissue microarray (TMA) IHC in 130 clinically annotated formalin-fixed paraffin-embedded serous tumors from Vanderbilt University Medical Center (VUMC). Staining intensity (1: weak; 2: moderate; 3: strong) and percent of positive nuclei (0-100) were multiplied to yield an H score for NR4A1 expression. Pearson correlation coefficients were determined for mRNA expression of cyclin E and BRD4 in 307 TCGA tumors (RSEM V2 data extracted from the Broad Firehose database) and protein expression of cyclin E and BRD4 in 130 serous ovarian tumors. CCNE1 and BRD4 expression in relation to platinum sensitivity were evaluated using the Mann-Whitney t test. RESULTS: The Cancer Genome Atlas (TCGA) demonstrated about 20% of high-grade serous EOC harbor amplifications in CCNE1 and BRD4. BRD4 amplification overlaps with CCNE1 amplification in 26/57 (46%) of high-grade serous EOC of the TCGA. Immunostaining for cyclin E and BRD4 in 130 serous ovarian tumors on a tissue microarray yielded intermediate-to-high staining of CCNE1 in 52.1% of tumors and intermediate-to-high staining of BRD4 in 71.6% of tumors. Protein expression by IHC between CCNE1 and BRD4 was positively correlated, r= 0.25, (p =0.005). High expression of CCNE1 was associated with platinum resistance (p = 0.023). High BRD4 expression was not associated with platinum resistance (p=0.95). CONCLUSION: TCGA mRNA and TMA IHC expression analysis suggest that a subset of serous ovarian tumors have high levels of CCNE1 and BRD4 expression. High CCNE1 expression is associated with poor prognosis and platinum resistance. High BRD4 expression is not associated with platinum resistance in this cohort. Future studies are warranted to evaluate the subset of tumors with elevated expression of both CCNE1 and BRD4 in relation to platinum resistance and clinical outcomes. Citation Format: Shariska Petersen, Andrew J. Wilson, Dineo Khabele. CCNE1 AND BRD4 EXPRESSION AND PLATINUM RESISTANCE IN HIGH-GRADE SEROUS OVARIAN CANCERS [abstract]. In: Proceedings of the 12th Biennial Ovarian Cancer Research Symposium; Sep 13-15, 2018; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2019;25(22 Suppl):Abstract nr GMM-046.