Abstract 2846: Association of cyclin E1 expression with genomic instability in ovarian cancer

Abstract Background: Cyclin E1 (CCNE1) expression has been associated with replicative stress and defects in double-strand break repair in multiple tumor types; however, this has yet to be demonstrated in ovarian cancer. Herein, we describe CCNE1 DNA amplification (AMP), messenger RNA (mRNA) expression, and cyclin E1 protein expression in 2 large cohorts of high-grade serous ovarian cancer (HGSOC) (The Cancer Genome Atlas [TCGA] and Caris Life Sciences, Phoenix, AZ, USA). Methods: 8127 HGSOC samples were analyzed by next-generation sequencing (NextSeq, 592 genes or NovaSeq, whole exome sequencing) and RNA (NovaSeq, whole transcriptome sequencing) (Caris Life Sciences). For genomic loss of heterozygosity (LOH), 22 autosomal chromosomes were split into 552 segments and the LOH of single nucleotide polymorphisms within each segment was calculated (LOH-H ≥16%). Homologous repair deficient (HRD+/−) status was determined by high genomic scar score (GSS) or BRCA1/2 mutant (MT) [HRD+], or low GSS and BRCA1/2 wild-type (WT) [HRD−], respectively. GSS was calculated from large-scale state transitions (LSTs) and LOH (GSS-H ≥46). 1177 samples from TCGA were also included in this analysis. Results: In the Caris data set, HGSOC CCNE1 AMP was significantly more frequent in BRCA1/2 WT HGSOC tumors (CCNE1 AMP: 4.88% BRCA1/2 MT vs 21% BRCA1/2 WT; P<0.0001), as reported in other studies. Additionally, median expression of CCNE1 mRNA was higher in BRCA1/2 WT samples when compared with BRCA1/2 MT samples (1.11-fc; P<0.0001). Median CCNE1 mRNA was higher in HRD− HGSOC compared with HRD+ HGSOC (Caris: 1.11-fc, P<0.0001; TCGA: P<0.0001). In both data sets, CCNE1 AMP was associated with lower global LOH prevalence (CCNE1-AMP %: 22.6% in LOH-L vs 13.9% LOH-H in Caris data, P<0.0001; TCGA, P<0.0001). However, there was a significant increase in CCNE1 mRNA expression in LOH-H compared with LOH-L HGSOC Caris samples (1.27-fc, P<0.0001). There were no associations between CCNE1 AMP or RNA/protein expression and LST in either data set, or with telomeric allelic imbalance score in TCGA. CCNE1 AMP was associated with aneuploidy in TCGA (P<0.001). We also examined an independent set of commercial ovarian cancer samples for CCNE1 protein and pH2AX expression by immunohistochemistry to evaluate for an association with double-strand breaks, which will be included in the presentation. Conclusion: Together, these data demonstrated that CCNE1 AMP and RNA/protein expression were associated with various types of replicative stress in HGSOC. These data warrant further investigation on the impact of CCNE1 AMP and CCNE1 expression on clinical outcomes. Citation Format: Ajay Obla, Michelle Kinder, Chifei Sun, Heather Bullins, Cynthia Timmers, Ming Poi, Sharon Wu, Edoardo Missiglia, Bettina Bisig, Krisztian Homicsko. Association of cyclin E1 expression with genomic instability in ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 2846.