BRCAness, Homologous Recombination Deficiencies, and Synthetic Lethality.

Junko Murai, Yves Pommier

Cancer research 2023 Apr 14

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The concept of "BRCAness" was first described in 2004 to define the situation in which a homologous recombination repair (HRR) defect in a tumor relates to and phenocopies BRCA1 or BRCA2 loss-of-function mutations. Soon after the discovery of synthetic lethality of PARP1/2 inhibitors in BRCA1- or BRCA2-deficient cells, McCabe and colleagues extended the concept of BRCAness to homologous recombination deficiency (HRD) by studying the sensitivity of cancer cells to PARP inhibitors. They genetically revealed that deficiency in HR-related genes (RAD51, RAD54, DSS1, and RPA1), DNA damage signaling genes (ATR, ATM, CHK1, CHK2, and NBS1), or Fanconi anemia-related genes (FANCD2, FANCA, and FANCC) conferred sensitivity to PARP inhibitors. Thus, cells acquire BRCAness either by genetic inactivation of the BRCA or HRD genes. Here, we briefly review how genomic profiling can identify BRCAness and deficiencies in HRD genes and the current difficulty to apply BRCAness/HRD in the clinic. We also discuss how BRCAness relates to HRD and the utility of evaluating BRCAness/HRD to select therapies with PARP inhibitors (olaparib, rucaparib, niraparib, talazoparib, pamiparib, fuzuloparib), topoisomerase I (TOP1) inhibitors (irinotecan, topotecan, and tumor-targeted TOP1 inhibitors), and platinum derivatives (cisplatin and carboplatin). See related article by McCabe and colleagues, Cancer Res 2006;66:8109-15. ©2023 American Association for Cancer Research.