Double-strand breaks (DSBs) in the DNA can happen between 10 and 50 times per cell per day, depending on the cell cycle and the tissue type. Two major mechanisms exist to repair those highly toxic DSBs: homologous recombination (HR) and non-homologous end joining (NHEJ). Homologous recombination is a high-fidelity pathway in which the original DNA sequence is restored using a matching DNA strand template for the repair process. The non-homologous end joining, in contrast, is an error-prone repair pathway, which repairs the loose ends of a broken double-stranded DNA by sealing them together. Consequently, the original DNA sequence is not preserved in this NHEJ pathway.
If the HR pathway is not functioning correctly, DSBs can only be repaired by the error-prone NHEJ pathway. This pathway leads to increased genomic instability as mutations accumulate. Genome instability and mutations are one of the hallmarks of cancer. Thus, cells with a dysfunctional HR pathway can play a crucial role in carcinogenesis and tumor progression. A dysfunctional HR pathway is also known as homologous recombination deficiency (HRD). The HRD status of a cell – whether it has a functioning HR pathway or not – can be vital for therapeutic interventions.
Two aspects need to be considered when assessing the HRD status. One cause of HRD is mutations in the breast cancer susceptibility genes 1 and 2 (BRCA1 and BRCA2). These two genes play a pivotal role in the homologous recombination repair mechanism. If mutations compromise the genes’ function, HR repair might not be possible anymore, resulting in the error-prone NHEJ as a repair pathway. As mentioned, the NHEJ pathway increases genomic instability as mutations accumulate. The assessment of genomic instability is the second aspect of the HRD status. Together with the genomic instability, large-scale structural rearrangements or aberrations, such as the loss of heterozygosity (LOH), large-scale state transitions (LSTs), or telomeric allelic imbalances (TAIs), are measurable genomic aberrations. In contrast to BRCA1 or BRCA2 mutations, which are the cause of HRD, genomic instability is the measurable consequence of HRD, provided as an HRD score. The HRD status of a cell – whether it is HRD positive or negative – depends on the technique used to determine the HRD score. Those techniques differ and cannot be directly compared as they are based on different clinical validation studies. Different cut-offs are defined in clinical practice to deduce the HRD status from the HRD score.
As it is now more apparent how the HRD status of a cell or a tumor can be determined, we can focus on its consequences for treatment options. HRD-positive tumors are sensitive to PARP inhibitors. PARP is the poly-(adenosine diphosphate [ADP]-ribose) polymerase. It plays a pivotal role in the repair mechanism of DNA single-strand breaks. When PARP is inhibited, single-strand breaks cannot be repaired properly, resulting in double-strand breaks. HRD-positive cells are deficient in repairing those double-strand breaks properly with HR, and more mutations and genomic instability accumulate, eventually leading to the cell’s death. HRD-negative cells, such as normal, healthy cells, have a functioning homologous recombination repair system and can repair the double-strand breaks properly, leading to the cell’s survival. These cells are also called homologous recombination proficient (HRP). PARP inhibitors are approved as therapeutic options in ovarian, breast, pancreatic, and prostate cancer with HRD-positive tumors. Thus, assessing a tumor’s HR status can be crucial in the treatment decision.
Figure 1 | Homologous recombination deficiency has consequences for tumor therapies. Using PARP inhibitors in cells with single-strand breaks can lead to double-strand breaks. In normal cells, these double-strand breaks can be fixed by the homologous recombination repair (HRR) system, leading to the cell’s survival. In tumor cells with mutations in the BRCA1 and BRCA2 genes and homologous recombination deficiency (HRD), the double-strand breaks can only be repaired by the non-homologous end joining, resulting in the accumulation of mutations, and eventually leading to the cell’s death.