BRCAness, Homologous Recombination Deficiencies, and Synthetic Lethality

by Selleckchem | Aug 13 2023

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).

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The concept of "BRCAness" was initially introduced in 2004 to describe tumors that exhibit a similar phenotype to those with BRCA1 or BRCA2 loss-of-function mutations. It refers to the situation where a tumor displays a homologous recombination repair (HRR) defect that resembles the effects of BRCA1 or BRCA2 mutations. This concept gained significance with the discovery of synthetic lethality of PARP1/2 inhibitors in BRCA1- or BRCA2-deficient cells.

In 2006, McCabe et al. expanded the concept of BRCAness by studying the sensitivity of cancer cells to PARP inhibitors. They found that not only BRCA-mutated cells but also those with deficiencies in other HR-related genes (such as RAD51, RAD54, DSS1, and RPA1), DNA damage signaling genes (such as ATR, ATM, CHK1, CHK2, and NBS1), or Fanconi anemia-related genes (such as FANCD2, FANCA, and FANCC) displayed sensitivity to PARP inhibitors. These genetic alterations in HRD genes can lead to cells acquiring BRCAness.

Genomic profiling techniques have been employed to identify BRCAness and deficiencies in HRD genes in tumors. These techniques involve analyzing the tumor's DNA to detect genetic alterations or signatures associated with HRD, such as somatic mutations, loss of heterozygosity, telomeric allelic imbalance, large-scale state transitions, or genomic scars. Various assays, including next-generation sequencing and specific gene panels, have been developed to assess HRD status and identify BRCAness.

Despite the potential clinical implications of BRCAness and HRD, there are challenges in applying these concepts in the clinic. One major difficulty lies in defining standardized criteria for identifying BRCAness and HRD across different tumor types. Additionally, there is a need to establish consistent methodologies and thresholds for genomic profiling assays to ensure accurate and reliable detection of BRCAness and HRD.

The assessment of BRCAness and HRD has gained importance in selecting appropriate therapies for cancer patients. PARP inhibitors, such as olaparib, rucaparib, niraparib, talazoparib, pamiparib, and fuzuloparib, have shown efficacy in tumors with BRCAness or HRD. These inhibitors exploit the synthetic lethality between PARP inhibition and defective HRR, leading to increased DNA damage and cell death specifically in BRCAness or HRD tumors. In addition to PARP inhibitors, other therapeutic options being explored for BRCAness or HRD tumors include topoisomerase I (TOP1) inhibitors like irinotecan and topotecan, as well as platinum derivatives such as cisplatin and carboplatin.

In summary, BRCAness refers to a homologous recombination repair defect in a tumor that phenocopies the effects of BRCA1 or BRCA2 loss-of-function mutations. Genomic profiling techniques can help identify BRCAness and deficiencies in HRD genes, but standardization and consistency remain challenges. The assessment of BRCAness and HRD status has implications for selecting targeted therapies, including PARP inhibitors, TOP1 inhibitors, and platinum derivatives, to improve treatment outcomes in cancer patients.