The ABC of HRD
Introducing the Oncomine™ Comprehensive Assay Plus HRD Sub-Panel
By Dr. Nicole Rossum
Introduction
Homologous recombination deficiency (HRD) refers to the inability of a cell to effectively repair DNA double-strand breaks (DSB) through the homologous recombination repair (HRR) pathway.
This deficiency is commonly due to mutations in key HRR genes like BRCA1, BRCA2, RAD51, and PALB2. As a result, cells accumulate DNA damage and develop genomic instability.
Cancers with HRD are particularly sensitive to DNA-damaging treatments such as:
- Platinum-based chemotherapies
- PARP inhibitors
These therapies have shown effectiveness in several cancers, including:
- Ovarian
- Breast
- Pancreatic
- Prostate
BRCA, HRR & HRD: Their Role in Cancer
There are two major pathways for repairing DNA double-strand breaks (DSBs):
- Non-Homologous End-Joining (NHEJ) – a fast but error-prone method
- Homologous Recombination (HR) – a more accurate, gene-driven repair method
Genes involved in HR include BRCA1, BRCA2, ATM, PALB2, RAD51, and others.
Mutations in any of these genes can result in HRD. A tumour that can't use HR properly relies on the less accurate NHEJ pathway. This leads to:
- Genomic instability
- Genomic scarring
These are key markers for identifying HRD-positive tumours.
Measuring HRD
The HRD phenotype includes both the cause and the consequence:
Causes
Identified by sequencing genes in the HRR pathway.
Consequences
Evaluated by assessing the genome for signs of instability, such as:
- Loss of heterozygosity (LOH): Intermediate regions (>15MB, < whole chromosome)
- Telomeric Allelic Imbalance (TAI): Imbalance at sub-telomeres, not crossing centromeres
- Large-Scale Transitions (LST): Chromosomal breaks (e.g. translocations, inversions)
Oncomine™ Comprehensive HRD Report Example
The Oncomine™ Comprehensive Assay Plus helps identify both HRR gene mutations and genomic scarring using the Genomic Instability Metric (GIM).
The GIM is a score that quantifies unbalanced changes in copy numbers across the genome.
A typical HRD report includes:
- GIM score
- HRR gene mutation profile
Conclusion
Testing for HRD is a crucial part of identifying cancers that are treatable with:
- PARP inhibitors
- Platinum-based therapies
Testing is available:
- As a standalone test
- As part of the Oncomine™ Comprehensive Assay Plus panel
Test Information
- Test mnemonic: HRD
- Clinical indications:
- Prostate carcinoma
- Ovarian carcinoma
- Endometrial carcinoma
- Genes tested:
ABRAXAS1, ATM, ATR, BARD1, BLM, BRCA1, BRCA2, BRIP1, CDK12, CHEK1, CHEK2, FANCA, FANCC, FANCD2, FANCE, FANCF, FANCG, FANCI, FANCL, FANCM, MRE11, NBN, PALB2, PARP1, POLD1, POLE, PPP2R2A, PTEN, RAD51, RAD51B, RAD51C, RAD51D, RAD52, RAD54L, RNASE2A, RNASE2B, RNASE2C, RPA1, TP53, XRCC2, XRCC3 - Specimen type:
Formalin Fixed Paraffin Embedded Tissue (FFPE)- 6–8 normal slides (not charged)
- 10 micron thick unstained recuts
- Turnaround time: 14 working days
- Contact: ngs@ampath.co.za
- Published: May 2025