Homologous recombination deficiency status-based classification of high-grade serous ovarian carcinoma

Abstract

Homologous recombination repair (HRR) pathway deficiency (HRD) is involved in the tumorigenesis and progression of high-grade serous ovarian carcinoma (HGSOC) as well as in the sensitivity to platinum chemotherapy drugs. In this study, we obtained data from The Cancer Genome Atlas (TCGA) on HGSOC and identified scores for the loss of heterozygosity, telomeric allelic imbalance, and large-scale state transitions, and calculated the HRD score. We then investigated the relationships among the score, genetic/epigenetic alterations in HRR-related genes, and the clinical data. We found that BRCA1/2 mutations were enriched in the group with HRD scores ≥63. Compared with the groups with scores ≤62, this group had a good prognosis; we thus considered HRD scores ≥63 to be the best cutoff point for identifying HRD cases in HGSOC. Classification of HGSOC cases by the HRD status revealed a better prognosis for HRD cases caused by genetic alterations (genetic HRD) than those caused by epigenetic changes and those caused by undetermined reasons (p = 0.0002). Among cases without macroscopic residual tumors after primary debulking surgery, 11 of 12 genetic HRD cases survived after the median observation period of 6.6 years, showing remarkably high survival rates (p = 0.0059). In conclusion, HGSOC can be classified into subtypes with different prognoses according to HRD status. This classification could be useful for personalized HGSOC treatment.

Identification of biomarkers complementary to homologous recombination deficiency for improving the clinical outcome of ovarian serous cystadenocarcinoma

“…Patients with NF1 gene loss-of-function mutations will progress to RAS hyperactivity and tumorigenesis [30,31]. The availability of small molecule compounds (such as selumetinib and imatinib) that target RAS signaling implied in the pathogenesis of plexiform neuro bromas [15,16] has led to multiple clinical trials, and FDA has approved Koselugo (selumetinib) for the treatment of pediatric patients with NF1 mutations [32]. CDK12 (Cyclin-dependent kinase 12) is a kinase involved in the regulation of the cell cycle and the regulation of transcriptional elongation of many DNA-damageresponse genes.…”

“…Telomeric Allelic Imbalance (TAI) was de ned as the number of regions with allelic imbalance which extend to the sub-telomere but do not cross the centromere [14]. The HRD score was de ned as the sum of TAI, LST, and LOH scores [15]. The HRD score of each patient was shown in Supplementary Table 1.…”

Biomarkers in Triple-Negative Breast Cancer: State-of-the-Art and Future Perspectives

“…Instead of quantifying the effect of genetic variation in the HR pathway, researchers have developed methods to score the competency of the HR pathway. Three scoring systems have emerged: HRD-loss of heterozygosity (HRD-LOD), HRD-large-scale transition (HRD-LST), and HRD-telomeric allelic imbalance (HRD-TAI) [ 41 , 42 , 43 ].…”

New Perspectives for Resistance to PARP Inhibitors in Triple-Negative Breast Cancer

“…TNBC is characterized by chromosomal instability resulting from homologous recombination repair (HRR) pathway deficiency (HRD) (36). The common causes of HRD include germline BRCA1/2 mutations, BRCA gene promoter methylation, and any genetic mutations of the HRR pathway (37). Some mutated-genes disrupting HRR pathway, including ATM, ATR, PALB2 and CHEK1/2, are the cortical elements that induce irreversible DNA damage and lead to synthetical mortality due to PARPi in TNBC treatment settings (38).…”