Dynamically Accumulating Homologous Recombination Deficiency Score Served as an Important Prognosis Factor in High-Grade Serous Ovarian Cancer

Abstract

Background: The homologous recombination (HR) pathway defects in cancers induced abrogation of cell cycle checkpoints, resulting in the accumulation of DNA damage, mitotic catastrophe, and cell death. Cancers with BRCA1/2 loss and other accumulation of similar genomic scars resulting in HRD displayed increased sensitivity to chemotherapy. Our study aimed to explore HRD score genetic mechanisms and subsequent clinical outcomes in human cancers, especially ovarian cancer.Methods: We analyzed TCGA data of HRD score in 33 cancer types and evaluated HRD score distribution and difference among tumor stages and between primary and recurrent tumor tissues. A weighted gene co-expression network analysis (WGCNA) was performed to identify highly correlated genes representing essential modules contributing to the HRD score and distinguish the hub genes and significant pathways. We verified HRD status predicting roles in patients’ overall survival (OS) with univariate and multivariate Cox regression analyses and built the predicting model for patient survival.Results: We found that the HRD score increased with the rise in tumor stage, except for stage IV. The HRD score tended to grow up higher in recurrent tumor tissue than in their primary counterparts (p = 0.083). We constructed 15 co-expression modules with WGCNA, identified co-expressed genes and pathways impacting the HRD score, and concluded that the HRD score was tightly associated with tumor cells replication and proliferation. A combined HRD score ≥42 was associated with shorter OS in 33 cancer types (HR = 1.010, 95% CI: 1.008–1.011, p < 0.001). However, in ovarian cancer, which ranked the highest HRD score among other cancers, HRD ≥42 cohort was significantly associated with longer OS (HR = 0.99, 95% CI: 0.98–0.99, p < 0.0001). We also built a predicting model for 3 and 5 years survival in HGSC patients.Conclusion: A quantitative HRD score representing the accumulated genomic scars was dynamically increasing in proliferating tumor cells since the HRD score was tightly correlated to tumor cell division and replication. We highlighted HRD score biomarker role in prognosis prediction of ovarian cancer.

Therapeutic targeting of DNA damage repair pathways guided by homologous recombination deficiency scoring in ovarian cancers

“…It is noteworthy that a high HRD score in OvCa often predict better prognosis unlike other cancers [220]. OvCa patients with HRD are more likely to obtain clinical benefit from DNA damage/repair‐targeted therapy.…”

RAD54B mutations enhance the sensitivity of ovarian cancer cells to poly(ADP-ribose) polymerase (PARP) inhibitors

“…In addition, scholars and oncologists have recently proposed a concept of HRD scoring for targeted and individualized therapy for ovarian cancer patients [70][71][72]. PARP inhibitor therapies are preferred for patients with higher HRD scores to achieve better outcome [71,72]. HRD scoring is heavily dependent on HRD gene panel, in which RAD54B is not currently included.…”

“…In view of the superior effects, PARPis were approved for use in the first line and early maintenance therapy along with the new data ( 67 , 68 , 69 ). In addition, scholars and oncologists have recently proposed a concept of HRD scoring for targeted and individualized therapy for OvCa patients ( 70 , 71 , 72 ). PARPi therapies are preferred for patients with higher HRD scores to achieve better outcome ( 71 , 72 ).…”

AKR1B1 as a Prognostic Biomarker of High-Grade Serous Ovarian Cancer

“…Recent studies showed that up to 50% of HGSC have a homologous recombination repair deficiency (HRD) [10,11]. Homologous recombination (HR) is one of the key mechanisms for the repair of double-strand breaks.…”

“…HGSC patients with HRD have a significantly prolonged progression-free survival and an increased responsiveness to chemotherapy, especially platinum agents, and PARP inhibitors. Therefore, HRD testing is an important prognostic and predictive biomarker in HGSC [10,11].Another targeted therapy for HGSC uses anti-angiogenic agents (bevacizumab) [8]. Additionally, serine/threonine-specific protein kinase inhibitors (afuresertib) show promising results [8].…”