Genes are fundamental instructions within our cells, guiding the production of proteins that carry out various bodily functions. These instructions are contained within DNA, a complex molecule constantly exposed to damage from internal cellular processes and external environmental factors. To maintain proper cellular health, cells possess systems designed to detect and repair this DNA damage. These repair mechanisms are crucial for preserving genetic integrity and preventing cellular dysfunction.
What are HRD Genes?
Homologous Recombination Deficiency (HRD) describes a cell’s impaired ability to accurately repair certain types of DNA damage, specifically double-strand breaks. This repair process, known as homologous recombination repair (HRR), is a high-fidelity pathway that uses an undamaged DNA template to precisely fix broken strands. When cells cannot perform HRR effectively, they become reliant on less accurate repair mechanisms, which can introduce errors into the DNA.
Genes involved in the HRR pathway are often referred to as HRD genes. Mutations in these genes can lead to the HRD state. Common examples include BRCA1 and BRCA2, well-known for their roles in DNA repair. Other genes whose alterations can contribute to HRD include PALB2, ATM, CHEK2, RAD51C, and BARD1.
These genes encode proteins that work together in a complex network to orchestrate the HRR process. For instance, BRCA1 and BRCA2 proteins recruit other repair proteins to the site of DNA damage and facilitate the exchange of genetic information during repair. When these proteins are not functional due to mutations, the cell’s capacity for accurate DNA repair is compromised.
Role in DNA Repair and Cancer Development
When HRD genes are mutated or dysfunctional, the cell’s ability to precisely repair double-strand DNA breaks is diminished. This forces the cell to use alternative, error-prone repair pathways, such as non-homologous end joining. These less accurate repair methods often result in deletions, insertions, or rearrangements of genetic material. The accumulation of these errors leads to genomic instability, a hallmark of cancer development.
Genomic instability means the cell’s DNA becomes highly disorganized and prone to further mutations, including those in genes that control cell growth and division. This uncontrolled accumulation of genetic changes increases the risk of cells transforming into cancerous ones. Individuals inheriting mutations in HRD genes, such as BRCA1 or BRCA2, have an elevated lifetime risk of developing specific types of cancer.
For example, mutations in BRCA1 and BRCA2 are linked to an increased risk of breast, ovarian, prostate, and pancreatic cancers. A person with a BRCA1 mutation might have up to a 72% lifetime risk of developing breast cancer and a 44% risk of ovarian cancer. These inherited predispositions underscore the impact of HRD gene function on maintaining genomic integrity and preventing disease. The compromised DNA repair capacity in these individuals creates an environment where cancer can more easily emerge and progress.
HRD as a Therapeutic Target
The presence of homologous recombination deficiency in cancer cells serves as a biomarker for guiding treatment decisions. This is particularly true for a class of drugs called PARP (Poly-ADP ribose polymerase) inhibitors. These inhibitors exploit a concept known as “synthetic lethality,” a strategy in cancer therapy.
Synthetic lethality occurs when the simultaneous disruption of two separate biological pathways leads to cell death, but the disruption of either pathway alone does not. In the context of HRD, cancer cells already have a defective homologous recombination repair pathway. PARP inhibitors work by blocking another DNA repair pathway that cancer cells with HRD rely upon for survival. By inhibiting PARP, these drugs create an insurmountable level of DNA damage in HRD-positive cancer cells, leading to their death, while largely sparing healthy cells that still possess an intact HRR pathway.
Identifying HRD status is performed through specific diagnostic tests. These tests analyze the tumor’s genetic makeup for specific patterns of genomic instability, often referred to as “genomic scars.” These scars include markers like loss of heterozygosity (LOH), telomeric allelic imbalance (TAI), and large-scale state transitions (LST). These genetic signatures indicate the tumor has been forced to use error-prone repair mechanisms due to underlying HRD. Patients whose tumors show these genomic scars are more likely to respond favorably to PARP inhibitor therapies.