HRD testing, or Homologous Recombination Deficiency testing, is a method used to identify deficiencies in a cell's ability to repair damaged DNA through homologous recombination. This testing helps assess the causes or effects of HRD.
Understanding HRD Testing
HRD testing is crucial in oncology as it helps in identifying patients who might benefit from specific targeted therapies, particularly PARP inhibitors. These inhibitors are effective in cancer cells with deficient HRR pathways because they exploit this deficiency to cause cell death.
Key Aspects of HRD Testing:
- Purpose: To identify tumors with a deficiency in the homologous recombination repair (HRR) pathway.
- Method: Tests can assess either the underlying genetic causes of HRD or the resulting genomic instability.
Biomarkers Included in HRD Testing (Referencing Figure 2):
| Category | Biomarker | Description |
|---|---|---|
| Genetic Causes | Germline pathogenic variants in BRCA1/2 | Inherited mutations in BRCA1/2 genes that directly impair HRR. |
| Somatic pathogenic variants in BRCA1/2 | Acquired mutations in BRCA1/2 genes within the tumor cells that impair HRR. | |
| Pathogenic variants in other genes involved in HRR (e.g., ATM, PALB2, RAD51) | Mutations in other critical HRR-related genes that contribute to deficiencies in the pathway. | |
| Genomic Instability | Genomic scars resulting from HRD (e.g., LOH, TAI, LST) | Indicators of chromosomal instability and mutations that occur due to HRD, such as loss of heterozygosity, telomeric allelic imbalance, and large-scale transitions. |
How HRD Tests are Performed:
- Genetic Sequencing: Identifies germline (inherited) and somatic (acquired within the tumor) mutations in genes like BRCA1, BRCA2, and other genes involved in HRR, such as ATM, PALB2, RAD51, and more.
- Genomic Instability Assessment: Examines the tumor's DNA for signatures or "scars" that indicate HRD. These include:
- Loss of Heterozygosity (LOH): Loss of one copy of a gene, often associated with tumor suppressor genes.
- Telomeric Allelic Imbalance (TAI): Imbalance in allele frequency near telomeres, indicating chromosomal instability.
- Large-Scale Transitions (LST): Extensive structural alterations in the chromosomes, reflecting severe genetic damage.
Clinical Implications
- Treatment Decisions: Results from HRD tests guide treatment decisions. Patients with HRD-positive tumors may be better candidates for PARP inhibitors.
- Prognosis: HRD status can also be an important factor for determining disease prognosis and risk assessment.
In summary, HRD testing helps identify patients with impaired DNA repair systems, providing crucial information for targeted therapy and personalized medicine in oncology.
