What Is Homologous Recombination Deficiency? Testing and Its Importance in Cancer

Homologous recombination deficiency (HRD) means that a cell cannot repair DNA damage through homologous recombination. HRD leads to genomic instability, which can contribute to the development of various cancers.

What Is Homologous Recombination?

Homologous recombination is a cellular pathway involved in DNA breakage and repair, helping maintain genetic information accurately. Recombination occurs between homologous chromosomes, which are similar copies, allowing exchange or repair of genetic material. This pathway can prevent genetic diseases and plays an important role in normal cell multiplication.

Homologous recombination is one type of DNA recombination.

DNA recombination means rearranging or changing DNA within a cell. The process is used to reorganise or repair its genetic material.

There are several types:

1. Homologous recombination: a pathway that exchanges matching DNA regions between two homologous chromosomes to rearrange or repair genetic material.

2. Site-directed recombination: a pathway used to change a particular gene or DNA region at a specific location, for genetic engineering or gene therapy.

3. Non-homologous recombination: a pathway that mixes two different DNA regions. It changes genetic material and may cause genetic diseases.

What Is Homologous Recombination Deficiency, and Which Cancers Does It Affect?

Homologous recombination deficiency (HRD) disrupts the process that cells normally use. Errors develop in the genetic material, and when these DNA errors accumulate, they may trigger normal cell multiplication or death. HRD is particularly important in ovarian and breast cancers because mutations in the BRCA1 and BRCA2 genes are important drivers, and these genes are essential for homologous recombination. People with BRCA1 and BRCA2 inherited and/or somatic mutations therefore develop HRD and have an increased risk of potentially hereditary cancers such as breast and ovarian cancer. HRD may also play a role in other tumours, including endometrial, prostate and pancreatic cancers.

Why Is It Important to Identify HRD in Cancer?

HRD testing is recommended in all patients with ovarian cancer and triple-negative breast cancer to assess suitability for newer cancer drugs called PARP inhibitors.

PARP inhibitorsare effective when DNA repair is impaired. Mutations in BRCA1 and BRCA2 are among the cellular processes most often associated with defective DNA repair.

Numerous clinical studies have shown that around 50% of ovarian cancer patients and 35-40% of triple-negative breast cancer patients may benefit from PARP inhibitors.

Since 2014, the FDA has approved four PARP inhibitors: olaparib, niraparib, rucaparib and talazoparib. They are approved for 4 cancer types: ovarian, prostate, pancreatic and breast cancer.

How Is HRD Tested?

Several tests can identify homologous recombination deficiency (HRD).

1. RediScore® is a genetic test developed to estimate HRD by analysing tumour genomic instability. It uses SNP (Single Nucleotide Polymorphism) technology, a standard method for analysing abnormal chromosomal structures resulting from homologous recombination deficiency. Combined with analysis of tumour BRCA1 / 2 mutations, it provides comprehensive information about HR pathway function.
   

   RediScore® uses three biological parameters, also called "genomic scars", to calculate HRD:
   » LOH – Loss of Heterozygosity 
   » TAI – Telomeric Allelic Imbalance
   » LST – Large-Scale Transitions

2. DNA sensitivity tests: these measure cells’ sensitivity to DNA damage. Sensitivity is increased in HRD cells, so such tests yield positive results when HRD is present.

3. Replication restriction enzyme genomic analysis (REGA): this technique analyses recombination processes in the cellular genome. REGA results are abnormal in cells with HRD.

4. Immunohistochemical (IHC) analysis: these tests identify the presence or absence of BRCA1 or BRCA2 proteins. Cells with HRD may lack BRCA1 or BRCA2 proteins.

5. Fluorometric in situ hybridisation (FISH): these tests determine BRCA1 or BRCA2 gene copy numbers. HRD cells may have fewer copies of BRCA1 or BRCA2.