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

Abstract

Background: 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.

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 TP53 pathogenic mutations in patients had 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 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, TP53 HRD-high mutation and HRD common mutation combinations showed the highest AUC values (0.80) in predicting HRD status.

Conclusions: TP53-specific mutation combinations predict the HRD status of patients, indicating that TP53 pathogenic mutations could serve as a potential biomarker for poly-ADP-ribose polymerase (PARP) inhibitors in breast cancer patients.

Keywords

next-generation sequencing / homologous recombination deficiency / TP53 / breast cancer

Ethical declaration

The study was conducted in accordance with the Helsinki Declaration. Patient records were anonymized prior to analysis. This study was approved by the Institutional Review Board of Sun Yat-sen Memorial Hospital (NO. SYSKY-2023-458-01).

Acknowledgements

This study was supported by funding from the National Natural Science Foundation of China (Grants No. 82203435, 82203703, 82203141, and 82102865), Guangdong Basic and Applied Basic Research Foundation (Grant No. 2021A1515111138), Guangzhou Science and Technology Plan Project Support (Grant No. 2023A04J2103), and the China Postdoctoral Science Foundation (Grants No. 2022M713576 and 2022T150757).

Author contributions

Study administration, validation, and design: J.Z., S.F., and J.L. Methodology, acquisition, and interpretation of data: all authors. Writing-original manuscript: Y.H. Study supervision: J.L. All authors read and approved the final manuscript.

Supplementary data

Supplementary data is available at PCMEDI online.

Conflict of interest

None declared.

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