Functional RECAP (REpair CAPacity) assay identifies homologous recombination deficiency undetected by DNA-based BRCAness tests.
Van Hoeck, Arne
Sieuwerts, Anieta M
Verkaik, Nicole S
Ladan, Marjolijn M
van Deurzen, Carolien HM
Linn, Sabine C
Springer Science and Business Media LLC
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Meijer, T. G., Nguyen, L., Van Hoeck, A., Sieuwerts, A. M., Verkaik, N. S., Ladan, M. M., Ruigrok-Ritstier, K., et al. (2022). Functional RECAP (REpair CAPacity) assay identifies homologous recombination deficiency undetected by DNA-based BRCAness tests.. Oncogene, 41 (26), 3498-3506. https://doi.org/10.1038/s41388-022-02363-1
Germline BRCA1/2 mutation status is predictive for response to Poly-[ADP-Ribose]-Polymerase (PARP) inhibitors in breast cancer (BC) patients. However, non-germline BRCA1/2 mutated and homologous recombination repair deficient (HRD) tumors are likely also PARP-inhibitor sensitive. Clinical validity and utility of various HRD biomarkers are under investigation. The REpair CAPacity (RECAP) test is a functional method to select HRD tumors based on their inability to form RAD51 foci. We investigated whether this functional test defines a similar group of HRD tumors as DNA-based tests. An HRD enriched cohort (n = 71; 52 primary and 19 metastatic BCs) selected based on the RECAP test (26 RECAP-HRD; 37%), was subjected to DNA-based HRD tests (i.e., Classifier of HOmologous Recombination Deficiency (CHORD) and BRCA1/2-like classifier). Whole genome sequencing (WGS) was carried out for 38 primary and 19 metastatic BCs. The RECAP test identified all bi-allelic BRCA deficient samples (n = 15) in this cohort. RECAP status partially correlated with DNA-based HRD test outcomes (70% concordance for both RECAP-CHORD and RECAP-BRCA1/2-like classifier). RECAP selected additional samples unable to form RAD51 foci, suggesting that this functional assay identified deficiencies in other DNA repair genes, which could also result in PARP-inhibitor sensitivity. Direct comparison of these HRD tests in clinical trials will be required to evaluate the optimal predictive test for clinical decision making.
Article, /631/67/1347, /631/337/1427/2190, /38/23, /96/63, /13/1, article
KWF Kankerbestrijding (Dutch Cancer Society) (EMCR 2014-7048, EMCR 2008-4045)
External DOI: https://doi.org/10.1038/s41388-022-02363-1
This record's URL: https://www.repository.cam.ac.uk/handle/1810/338506