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.
Highlights
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
When germline BRCA1/2 mutations and somatic BRCA1/2 mutations were analyzed together as BRCA mutations, it was found that BRCA mutation cases had high HRD scores (p < 0.0001, Fig. 1C)
Our contributions are as follows: (1) establishing a cutoff value to identify HRD from the analysis of HGSOC data alone (2); a comprehensive analysis of HRR pathway genes (3); proposal of a classification method for HRD cases according to cause; and (4) integration of residual tumor data
Summary
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. 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. In The Cancer Genome Atlas (TCGA) project, about half of HGSOC cases are reported to have HRD due to an HRR pathway abnormality[4]. We investigated the connection between HRD status and HRR pathway gene abnormalities in HGSOC data in the TCGA, and we show that HGSOC can be classified according to HRD status into subtypes with different prognoses
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