CCNE1 and BRD4 co-amplification in high-grade serous ovarian cancer is associated with poor clinical outcomes

Shariska Petersen,Andrew J Wilson,Jeff Hirst,Katherine F Roby,Oluwole Fadare,Marta A Crispens,Alicia Beeghly-Fadiel,Dineo Khabele

doi:10.1016/j.ygyno.2020.01.038

Abstract

ObjectiveHigh-grade serous ovarian cancer (HGSOC) is the most common and lethal histological subtype of epithelial ovarian cancer. HGSOC with cyclin E1 gene (CCNE1) amplification and bromodomain and extraterminal 4 (BRD4) amplification have been associated with poor outcomes. Our objective was to evaluate clinical outcomes of HGSOC with co-amplification of CCNE1 and BRD4 and high protein expression of cyclin E and BRD4. MethodsCopy number amplification data were extracted from The Cancer Genome Atlas (TCGA) for 579 HGSOC. Reverse phase protein array (RPPA) TCGA data were used to determine cyclin E and BRD4 protein expression in 482 HGSOC. Cyclin E and BRD4 protein expression by immunohistochemistry (IHC) was evaluated in a tissue microarray (TMA) of 110 HGSOC. Measured clinical outcomes were survival and platinum sensitivity. ResultsOf 30% of HGSOC with amplifications in CCNE1 or BRD4, 8% have both CCNE1 and BRD4 amplification. Protein expression of cyclin E and BRD4 are positively correlated, both by RPPA (r = 0.23; p < 0.001) and by IHC (r = 0.21; p = 0.025). Patients with CCNE1 and BRD4 co-amplified HGSOC have worse overall survival than patients without amplifications, 39.94 vs 48.06 months (p = 0.029). High protein expression of cyclin E, but not BRD4, was associated with poor overall survival (HR 1.62, 1.04–2.53, p = 0.033) and platinum resistance (p = 0.016). ConclusionHGSOC with CCNE1 and BRD4 co-amplification are associated with poor overall survival. Further studies are warranted to determine the use of protein expression by IHC as a surrogate marker for CCNE1 and BRD4 co-amplified HGSOC.

Highlights

cyclin E1 gene (CCNE1) and bromodomain and extraterminal 4 gene (BRD4) are co-amplified with high protein expression levels in HGSOC
CCNE1 amplification was detected in 48% (47/98) of HGSOC that harbored a BRD4 amplification (Fig. 1A)
A total of 176 (30%) HGSOC harbored an amplification in CCNE1 and/or BRD4 and 47 (8%) have both CCNE1 and BRD4 amplifications (Fig. 1B)

Summary

Introduction

S. Petersen et al / Gynecologic Oncology 157 (2020) 405–410 care for advanced staged disease includes radical tumor debulking surgery and platinum-based chemotherapy. ADP ribose polymerase inhibitors (PARPi) are FDA-approved drugs that significantly improve clinical outcomes, especially in women with germline BRCA1/2 mutations [2,3,4,5,6,7,8,9]. Tumors with BRCA1/2 mutations are, by definition, homologous recombination (HR) deficient. PARPi induce synthetic lethality in BRCA1/2 mutated tumors by inhibiting repair of single strand DNA breaks, resulting in double strand breaks that require the HR pathway for efficient DNA repair [10]. In BRCA1/2 mutated HR deficient tumors, unrepaired DNA causes cancer cell death and a favorable clinical response [11]

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Conclusion