Abstract GMM-031: CLINICAL PATHOLOGIC EXPRESSION OF CELL CYCLE REGULATORY COMPLEXES IN HIGH GRADE SEROUS OVARIAN CARCINOMA
Authors: Iness Audra N. , Rubinsak Lisa , Chaoul Jessica , Dozmorov Mikhail , Uram-Tuculescu Cora , Litovchick Larisa , Temkin Sarah 
Published: June 2021

INTRODUCTION: Cell cycle control is an important determinant of cancer progression and treatment response. Two key transcriptional regulatory complexes, DREAM and MMB, ensure coordinated cell cycle dependent gene expression. Though these complexes contain the same protein core called MuvB, they have opposing functions. The DREAM (DP, RB-like, E2F, and MuvB) complex represses over 800 cell cycle genes in G0/G1 and the MMB (Myb-MuvB) complex promotes mitotic gene expression. High expression of B-Myb, an oncogenic transcription factor involved in the MMB complex, is associated with cell cycle deregulation and poor prognosis in several cancers, including ovarian cancer. High B-Myb expression disrupts DREAM formation in human cell lines, resulting in increased proliferation. Previous analysis of TCGA data showed that MYBL2 (encoding B-Myb) undergoes gene copy number gain in 55% of high grade serous ovarian cancer (HGSOC) tumor samples and is associated with poor overall survival. We sought to validate these findings with clinical specimens and to investigate the role of DREAM- and MMB-regulated gene expression in HGSOC patient outcomes.

METHODS: We used expression levels of DREAM-and MMB-controlled genes as a functional readout for the status of these opposing transcriptional regulators. This retrospective study utilized tissue bank surgical pathology and cytology samples taken from 52 HGSOC lesions. RT-qPCR gene expression analysis was correlated to clinical and pathologic findings. Demographic information, follow-up, treatment, and outcomes data (age, Stage, optimal debulking, platinum sensitivity, survival) was obtained by chart review. Analyses of TCGA datasets were conducted in parallel.

RESULTS: RT-qPCR analysis of DREAM target genes (AURKA, KIF23, CCNB2, and FOXM1) revealed positive and significant correlations between MYBL2 and all genes tested: AURKA (ρ=0.4114, p&lt;0.01), KIF23 (ρ=0.4953, p&lt;0.001), CCNB2 (ρ=0.3278, p&lt;0.05), and FOXM1 (ρ=0.5033, p&lt;0.001). Stage at diagnosis, optimal debulking, platinum sensitivity and survival did not associate with high or low expression of target genes. High FOXM1 expression was associated with longer progression free survival (p&lt;0.01). High CCNB2 (encoding cyclin B2) showed a trend (p=0.0643) with decreased overall survival, with a median time difference of 20 months between high (26 months) and low (46 months) groups. Analysis of TCGA HGSOC datasets revealed that DREAM and MMB target genes were significantly upregulated in the presence of high B-Myb expression (Fisher's exact test, p&lt;0.01). The top 49 upregulated genes associated with high MYBL2 in HGSOC analysis have been previously annotated as DREAM target genes (χ2 with Yates correction p&lt;0.001).

CONCLUSIONS: Increased expression of selected cell cycle genes correlates to increased formation of MMB, and reduced DREAM assembly in HGSOC tissue. High expression of MYBL2 is associated with deregulated cell cycle gene expression programs in HGSOC. Larger scale studies would clarify the clinical prognostic value of the DREAM- and MMB-regulated gene expression.

Citation Format: Audra N. Iness, Lisa Rubinsak, Jessica Chaoul, Mikhail Dozmorov, Cora Uram-Tuculescu, Larisa Litovchick, Sarah Temkin. CLINICAL PATHOLOGIC EXPRESSION OF CELL CYCLE REGULATORY COMPLEXES IN HIGH GRADE SEROUS OVARIAN CARCINOMA [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-031.