TP53-specific mutations serve as a potential biomarker for homologous recombination deficiency in breast cancer: a clinical next-generation sequencing study

Abstract

TP53 mutations and homologous recombination deficiency (HRD) occur frequently in breast cancer. However, the characteristics of TP53 pathogenic mutations in breast cancer patients with/without HRD are not clear. Both tumor and paired blood DNA from 119 breast cancer patients were performed clinical next-generation sequencing (NGS) by a 520-gene panel. Mutations, tumor mutation burden (TMB), and genomic HRD scores were assessed from NGS data. All TP53 pathogenic mutations in patients were the somatic origin, which was associated with the protein expression of estrogen receptor and progestogen receptor. Compared to patients without TP53 pathologic mutations, patients with TP53 pathologic mutations had higher levels of HRD scores and different genomic alterations. The frequency of TP53 pathologic mutation was higher in the HRD-High group (HRD score≥42) relative to that in the HRD-Low group (HRD score<42). TP53 has different mutational characteristics between the HRD-Low and HRD-High groups. TP53-specific mutation subgroups had diverse genomic features and TMB. Notably, TP53 pathogenic mutations predicted the HRD status of breast cancer patients with an 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, TP53 HRD-High mutation and HRD common mutation combinations showed the highest AUC values (0.80) in predicting HRD status. TP53-specific mutation combinations predict the HRD status of patients, indicating that TP53 pathogenic mutations could serve as a potential biomarker for PARP inhibitors in breast cancer patients.