46P - Promising epi(genetic) biomarkers for ovarian tumor prognosis

Background

Ovarian cancer (OC) is the second most lethal gynecologic malignancy in the world. Most deaths are attributed to high-grade serous type OC (HGSOC) which typically presents at a late stage (FIGO III-IV). Currently, there are no reliable (epi)genetic biomarkers for OC.

Methods

Tumor tissue samples from 56 patients with gynecologic tumors (32 HGSOC, 15 other malignant gynecologic tumors, and 9 benign gynecologic tumors) were used for both DNA and RNA extraction. In all, a panel of 10 genes, including Notch pathway (NOTCH1-4, HES1, DLL1, and JAG2), Wnt pathway (CTNNB1, FBXW7) and chromatin remodeling complex SWI/SNF member ARID1A gene expression, was analyzed via RT-qPCR, as well as promoter methylation of ARID1A and homeobox (HOX) related genes (HOPX, ALX4, CDX2) analysis conducted using methylation specific PCR. ROC analysis was used to analyze biomarker prediction of HGSOC tumors, and LASSO algorithm used to select the best model for tumors prognosis.

Results

A significant reduction in CTNNB1, FBXW7, ARID1A, NOTCH1-4, DLL1, and HES1 gene expression was observed in OC patients when compared to benign cases (p < 0.03). Wnt gene, and Notch gene DLL1 and HES1 expression was also significantly decreased in HGSOC samples in comparison with other gynecologic tumors and Wnt genes also significantly decreased in HGSOC patients with FIGO stage IV tumors (CTNNB1 p = 0.02, FBXW7 p = 0.01). CDX2 and HOPX related gene promoter methylation was significantly higher in OC patients compared to benign cases (p = 0.02). ROC analysis of OC samples revealed HES1 as the best predictor of HGSOC vs other gynecologic malignancies (AUC = 0.84, sensitivity = 73%, specificity = 91%) while CDX2 was the best promotor methylation biomarker (AUC = 0.57, sensitivity = 67%, specificity = 47%). A combination of 7 biomarkers (NOTCH4, CTNNB1, JAG2, HES1 expression and HOPX, CDX2 and ARID1A promoter methylation status) showed perfect separation of HGSOC from other gynecologic cancers (AUC = 1).

Conclusions

Gene expression and promoter methylation status could be useful for ovarian tumor prognosis, however, a more extensive analysis of these biomarkers in a larger cohort and non-invasive samples is needed for further validation.

Editorial acknowledgement

Clinical trial identification

Legal entity responsible for the study

National Cancer Institute, Lithuania.

Funding

National Cancer Institute, Lithuania.

Disclosure

All authors have declared no conflicts of interest.