Homologous recombination deficiency can be identified by two strategies. You can look for mutations or other genomic alterations (e.g. promoter methylation) that cause homologous recombination deficiency or you can look for the effects of homologous recombination deficiency itself.1
The effect of homologous recombination deficiency can be assessed using a genomic instability test, and although the test will not exactly reveal what is causing the deficiency, the test will determine if homologous recombination deficiency is present. On the other hand, the causes of homologous recombination deficiency can be determined using a gene panel test. However, the test may not reveal the whole picture and it has a risk of missing some causes of homologous recombination deficiency.1
HRR gene panel test
- Looks for the cause of HRR loss1
- Identifies specific pathogenic mutations by looking for loss of function of key HRR genes including BRCA
HRD genomic instability test
- Looks for the effect of HRR loss1
- Quantifies genomic abnormalities that are characteristic of homologous recombination deficiency. Sometimes referred to as a genomic scar test.1 Allows investigation of homologous recombination deficiency regardless of cause
- Should be done in combination with BRCA testing2
Causes
Effects
There are a number of different mutations and other causes that may contribute to homologous recombination deficiency. However, instead of testing for these individually to identify the cause of homologous recombination deficiency, more patients can be identified and better informed treatment decisions may be made sooner if we look for the effect of these mutations.1,3
Testing for HRR mutations alone does not identify all cases of homologous recombination deficiency in ovarian cancers. However, the genomic instability assay or ‘scar test’ is a laboratory diagnostic test that is capable of identifying more ovarian cancers with homologous recombination deficiency. The genomic instability test should be performed in conjunction with a BRCA mutation test.1,2
Click here for more information on the concept of cause and effect
Measures of genomic instability
There are different approaches to measuring genomic instability. Genomic instability can be determined by assessing the extent of chromosomal aberrations such as loss of heterozygosity (LOH), telomeric allelic imbalance (TAI) or large-scale state transitions (LST)2
Some tests assess all three parameters of genomic instability, others evaluate LOH alone. Genomic instability tests should always be performed with a BRCA mutation test2,9
Loss of heterozygosity (LOH)
Is the presence of a single allele and refers to a specific type of genetic mutation where there is a loss of one normal copy of a gene or a group of genes11,12
There are two types of LOH12–14
- Copy number neutral LOH: a change in the gene without a change in the chromosomal copy number
- Deletion LOH: occurs as a result of copy number loss
Telomeric allelic imbalance (TAI)
Is a change in the 1:1 allele ratio at the end of the chromosome (telomere)13–15
TAI is similar to LOH, but the difference is that the structural change occurs specifically at the telomere15
Large-scale state transitions (LST)
Are defined as chromosomal breaks between adjacent regions of at least 10 megabases16
These can be caused by transfer of DNA from one chromosome to another chromosome, but can also be caused by inversions, deletions and duplications of DNA13,14,16,17
1. Pellegrino B, et al. ESMO Open 2019;4(2):e000480; 2. Myriad myChoice HRD Technical Specifications. Available at: https://myriad-web.s3.amazonaws.com/myChoice/downloads/myChoiceHRDTechSpecs.pdf (Accessed July, 2021); 3. Konstantinopoulos PA, et al. Cancer Discov 2015;5:1137–11541; 4. Ray-Coquard I, et al. Presented at European Society for Medical Oncology Annual Meeting 2019; 27th September – 1st October 2019; Barcelona, Spain; 5. Gonzalez-Martin A, et al. N Engl J Med 2019;381:2391–2402; 6. Mirza MR, et al. N Engl J Med 2016;385; 7. Hoppe M, et al. J Natl Cancer Inst 2018;110:704–713; 8. O’Connor MJ. Mol Cell 2015;60:547–560; 9. Foundation Medicine, Inc. FoundationFocus™ CDxBRCA LOH Technical Information Summary. Available at: https://www.accessdata.fda.gov/cdrh_docs/pdf16/P160018S001c.pdf (Accessed July, 2021); 10. Ray-Coquard I, et al. N Engl J Med 2019;381:2416–2428; 11. Ryland GL, et al. BMC Med Genom 2015;8:45; 12. Nichols CA, et al. Nat Commun 2020;11:2517; 13. Watkins J, et al. Breast Cancer Res 2014;16:211; 14. Den Brok W, et al. JCO Precision Oncology 2017. doi:10.1200/PO.16.00031; 15. Birkbak NL, et al. Cancer Discov 2012;2:366–375; 16. Popova T, et al. Cancer Res 2012;72:5454–5462; 17. Manié E, et al. Int J Cancer 2016;138:891–900