-specific mutations serve as a potential biomarker for homologous recombination deficiency in breast cancer: a clinical next-generation sequencing study.

BACKGROUND

mutations and homologous recombination deficiency (HRD) occur frequently in breast cancer. However, the characteristics of pathogenic mutations in breast cancer patients with/without HRD are not clear.

METHODS

Clinical next-generation sequencing (NGS) of both tumor and paired blood DNA from 119 breast cancer patients (BRCA-119 cohort) was performed with a 520-gene panel. Mutations, tumor mutation burden (TMB), and genomic HRD scores were assessed from NGS data. NGS data from 47 breast cancer patients in the HRD test cohort were analyzed for further verification.

RESULTS

All pathogenic mutations in patients had somatic origin, which was associated with the protein expression of estrogen receptor and progestogen receptor. Compared to patients without pathologic mutations, patients with pathologic mutations had higher levels of HRD scores and different genomic alterations. The frequency of pathologic mutation was higher in the HRD-high group (HRD score ≥ 42) relative to that in the HRD-low group (HRD score < 42). has different mutational characteristics between the HRD-low and HRD-high groups. -specific mutation subgroups had diverse genomic features and TMB. Notably, pathogenic mutations predicted the HRD status of breast cancer patients with an area under the curve (AUC) of 0.61. TP53-specific mutations, namely HRD-low mutation, HRD-high mutation, and HRD common mutation, predicted the HRD status of breast cancer patients with AUC values of 0.32, 0.72, and 0.58, respectively. Interestingly, HRD-high mutation and HRD common mutation combinations showed the highest AUC values (0.80) in predicting HRD status.

CONCLUSIONS

-specific mutation combinations predict the HRD status of patients, indicating that pathogenic mutations could serve as a potential biomarker for poly-ADP-ribose polymerase (PARP) inhibitors in breast cancer patients .