Promoter Methylation Changes in DNA Damage-Response Genes in Ovarian Cancer and Their Correlation with Prognosis

Abstract

Background: Ovarian cancer has a poor prognosis, and DNA damage-response (DDR) genes are associated with both its occurrence and prognosis. However, previous studies have mostly focused on genetic mutations, with no clear conclusions on epigenetic factors such as DNA methylation. Methods: In this study, we comprehensively investigated the relationship between promoter methylation of DDR genes and ovarian cancer prognosis. We performed combined multidata analysis of the promoter methylation, expression, homologous recombination defieiency (HRD) score, and drug sensitivity of 377 DDR genes in ovarian cancer by utilizing The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) datasets. We then validated abnormal promoter methylation and its relationship with overall survival in clinical samples. Results: Our analysis identified 52 methylation-driven DDR genes that exhibited abnormal expression due to abnormal promoter methylation. These genes are mostly related to BRCA1-related DNA damage repair and cell cycle regulatory pathways. Further studies revealed six of these genes, BRCA1, PTTG1, TTK, AURKA, CDC6, and E2F1, to be significantly associated with HRD scores. Among them, E2F1, PTTG1, and CDC6 are associated with drug sensitivity. Finally, we verified in 81 ovarian cancer samples that methylation of the promoter of these three genes was significantly associated with patient survival. Conclusions: Our study identified a large number of methylation-driven aberrantly expressed DDR genes in ovarian cancer, some of which affect disease prognosis. Levels of methylation of these gene promoters may serve as potential prognostic markers.

Keywords

• ovarian cancer
• dna damage response
• dna methylation
• prognosis
• promoter