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RAD51 as a functional biomarker for homologous recombination deficiency in cancer: a promising addition to the HRD

Lise M van Wijk1, Andreea B Nilas1, Harry Vrieling1

  • 1Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands.

Expert Review of Molecular Diagnostics
|December 16, 2021
PubMed
Abstract

Insights

Identifying homologous recombination deficiency (HRD) in carcinomas is crucial for PARP inhibitor (PARPi) therapy. This review covers current DNA-based and functional HRD tests, highlighting their strengths and weaknesses for clinical use.

Area of Science:

  • Oncology
  • Genetics
  • Molecular Biology

Background:

  • Carcinomas with homologous recombination (HR) pathway defects are sensitive to poly (ADP-ribose) polymerase inhibitors (PARPi).
  • Accurate identification of HR-deficient (HRD) carcinomas is clinically essential for effective PARPi treatment selection.
  • Current HRD tests include DNA-based methods (gene sequencing, genomic scars) and functional assays (RAD51 protein accumulation).

Purpose of the Study:

  • To provide a comprehensive overview of existing homologous recombination deficiency (HRD) testing methodologies.
  • To critically evaluate the advantages and disadvantages of various HRD detection approaches.
  • To assess the sensitivity, concordance, and predictive capacity of different HRD tests for therapy response.

Main Methods:

  • Review of current literature on homologous recombination deficiency (HRD) testing.
  • Comparative analysis of DNA-based HRD detection methods (e.g., BRCA mutation analysis, genomic scar identification).
  • Evaluation of functional HRD assays assessing RAD51 protein accumulation at DNA double-strand breaks.

Main Results:

  • Discussion of the sensitivity and concordance rates of various HRD tests in identifying deficient tumors.
  • Analysis of the capacity of different HRD testing strategies to predict patient response to PARP inhibitors.
  • Pros and cons of DNA-based versus functional HRD testing methodologies are presented.

Conclusions:

  • The increasing application of PARPi necessitates the integration of HRD testing into routine clinical practice.
  • Prioritization of HRD threshold calibration and clinical validation for both DNA-based and RAD51-based tests is recommended.
  • Standardized and validated HRD testing is crucial for optimizing PARPi therapy outcomes in cancer patients.
Keywords:
BRCA1BRCA2RAD51RAD51-FFPE testRECAP testgenomic scarshomologous recombination deficiencymutational signatures

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