298O The clinical significance of deregulated cyclin E1 in high grade serous ovarian cancer (HGSOC)

Abstract

Background Cyclin E1 protein is highly expressed in 30% ofHGSOC, and while CCNE1 amplification provides a plausible mechanism in about halfofcases, the driver andtheclinicalimpactofhighexpressioninnonamplifiedcasesispoorlyunderstood. ApossiblemechanismisdisrupteddegradationofcyclinE1,whichisnormally promotedbyFBXW7andtheproteasomepathway.InactivationofFBXW7israrelydue to mutations in ovarian cancer but is still possible due to epigenetic or enzymatic (USP28)inactivationofFBXW7bydeubiquitinationofitssubstrates(cyclinE1).We sought to define the likely drivers and significance ofderegulated cyclin E1 in 262 HGSOC samples obtained from patients enrolled in the Australian Ovarian Cancer Study(AOCS). Methods We used tissue microarrays and VENTANA BenchMark ULTRA to perform dual ISH (19q12 probe spanning the CCNE1 gene and INSR probe as chromosome 19 surrogate)andimmunohistochemistrytodetectcyclinE1(SantaCruz),FBXW7 (Spring Bioscience) and USP28 (Sigma Aldrich). Results Both CCNE1 amplification and USP28 expression significantly correlated to cyclinE1expression(p<0.0001,p<0.0001respectively)whileFBXW7didnot (p = 0.2). CCNE1 amplification and high cyclin E1 expression were both exclusive of BRCA1mutation(p<0.0001,0.0070),hadsignificantcorrelationswithoverallsurvival (OS,months),(28.3vs.45.6,P=0.028,HR0.6;30.9vs.45.6,P=0.028,HR0.67 respectively).However,innon-amplifiedhighcyclinE1 cases,noimpactonOSandPFS was noted. Similarly, FBXW7 and USP28 had no impact on PFS. However, in the high USP28subgroup,astatisticallysignificantdifferenceinOSbetweenhighandlowcyclin E1 expression (33.6 vs. 55.8, HR 0.5, p = 0.008) was noted. A trend towards worsened OS in lowFBXW7 subgroup was reported forhigh vs lowcyclin E1 expressers (30.9 vs. 48.5,HR0.6,p=0.07). Conclusions >HighexpressionofcyclinE1 inHGSOCislikelyduetogeneamplification as well as disrupted degradation by enzymatic inactivation ofFBXW7. High expression of cyclin E1 in conjunction with CCNE1 gene amplification and/or high USP28 expression are associated with unfavorable outcomes. These findings may be of importance for targeted therapy development in HGSOC. Legal entity responsible for the study The University ofMelbourne Funding Ventana Medical System Disclosure D. Aziz, D. Etemadmoghadam, G. Au-Yeung, A. Muranyi, I. Gresshoff, M. Christie, R.A. Hutchinson, D. Ferraro, S. Stanislaw, L.A. Henricksen, A. Tubbs, K. Shanmugam,D.Bowtell,P.M.Waring:VentanaMedicalSystemsareprovidingfunding to undertake this project