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

Date 16 December 2016
Event ESMO Asia 2016 Congress
Session Gynaecological cancers
Topics Ovarian Cancer
Translational Research
Presenter Diar Aziz
Citation Annals of Oncology (2016) 27 (suppl_9): ix94-ix103. 10.1093/annonc/mdw585
Authors D. Aziz1, D. Etemadmoghadam2, G. Au-Yeung3, A. Muranyi4, I. Gresshoff1, M. Christie1, R.A. Hutchinson1, D. Ferraro1, S. Stanislaw4, L.A. Henricksen4, A. Tubbs4, K. Shanmugam4, D. Bowtell5, P.M. Waring1
  • 1Pathology, University of Melbourne, 3010 - Parkville/AU
  • 2Cancer Genomics, PeterMacCallum Cancer Centre, 3010 - Parkville/AU
  • 3Medical Oncology, Peter MacCallum Cancer Center, 3002 - Melbourne/AU
  • 4Medical Innovation, Ventana Medical Systems, Inc., 85755 - Tucson/US
  • 5Cancer Genomics And Genetics Program, Peter MacCallum Cancer Centre, 3002 - Melbourne, VIC/AU

Abstract

Background

Cyclin E1 protein is highly expressed in 30% of HGSOC, and while CCNE1 amplification provides a plausible mechanism in about half of cases, the driver and the clinical impact of high expression in non amplified cases is poorly understood. A possible mechanism is disrupted degradation of cyclin E1, which is normally promoted by FBXW7 and the proteasome pathway. Inactivation of FBXW7 is rarely due to mutations in ovarian cancer but is still possible due to epigenetic or enzymatic (USP28) inactivation of FBXW7 by deubiquitination of its substrates (cyclin E1). We sought to define the likely drivers and significance of deregulated 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) and immunohistochemistry to detect cyclin E1 (Santa Cruz), FBXW7 (Spring Bioscience) and USP28 (Sigma Aldrich).

Results

Both CCNE1 amplification and USP28 expression significantly correlated to cyclin E1 expression (p 

Conclusions

High expression of cyclin E1 in HGSOC is likely due to gene amplification as well as disrupted degradation by enzymatic inactivation of FBXW7. 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.

Clinical trial indentification

Legal entity responsible for the study

The University of Melbourne

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: Ventana Medical Systems are providing funding to undertake this project