Characterization of mutational signatures of homologous recombination deficiency (HRD) in Chinese breast cancer.

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e15129 Background: Homologous recombination deficiency (HRD) is a common molecular characteristic of genomic instability and has been proved to be an important biomarker for personalized therapy decisions and stratified management in breast cancer. In this study, we explored the mutational features of HRD tumors identified by HRD score in Chinese breast cancer. Methods: Tumor tissue DNA from 68 breast cancer patients was isolated and sequenced by next-generation sequencing (NGS) technologies with AcornMed 808-genes panel. HRD score was calculated as an unweighted sum of loss of heterozygosity (LOH) score, telomeric allelic imbalance (TAI) score and large-scale state transition (LST) score by AcornHRD algorithm, and mutations in 39 homologous recombination (HR) related genes including BRCA1/2 were identified for each case. Results: Based on the mutation alternation profiles from our cohort, somatic BRCA1/2 mutations were present in 15 patients (22.1%) while 29 patients (42.6%) harbored one or more mutations in HR-related genes excluding BRCA1/2. Germline mutations of BRCA1/2 and other HR-related genes occurred in 11.8% and 4.4% of cases detected, respectively.In our cohort, the median HRD score was 40 (range from 3 to 92). Sixty-eight cases were divided into HRD-high or HRD-low group based on a cut-off value of ≥ 42 or < 42, with HRD-high group accounting for approximately 47% of our cohort, indicating the combination with HRD score yielded an increment of 26.5% in coverage of HRD within BRCA1/2 wildtype cases. The HRD-high group covered 82.4% of the BRCA-mutated cases and also showed higher mutation level of BRCA1/2-excluded HR genes than HRD-low group (p = 0.001). Prevalence of mutations in a total of 12 genes, including BRCA1(31.3% vs 5.6%, p = 0.009) and NBN (25% vs 5.6%, p = 0.038), were significant difference between HRD-high and HRD-low group. Besides, Cosmic Signature 1 (spontaneous deamination of 5-methylcytosine) and 5 (unknown) were existed in both groups, whereas Signature 6 (defective DNA mismatch repair) was only discovered in HRD-high group. Compared with HRD-low ones, copy number variations ratio was higher in HRD-high group (p = 0.031). Meanwhile, the patients with ERBB2 amplification (HER2+) showed a lower level of HRD score than HER2- ones. Conclusions: This study comprehensively delineated the genetic characteristics of HRD tumors, which suggests that HRD status marked by HRD score is strongly associated with BRCA1/2 and HR-related genes mutation as well as other genomic instability signatures, thus indicating its predictive value as a promising biomarker for DNA repair deficiency related drugs or therapies in Chinese breast cancer.