Table 1.
Examples of homologous recombination deficiency (HRD) scores discovered and presented in the literature
| Signature/algorithm name | Description & features | Reference |
|---|---|---|
| Myriad’s MyChoice HRD | Tested in ovarian tumors and 57 cell lines (breast and pancreatic) | (22) |
| Association between homologous recombination defects and genomic patterns of loss of heterozygosity (LOH) | ||
| The HRD score appears capable of detecting homologous recombination defects regardless of etiology or mechanism | ||
| Single Base Substitution Signatures (SBS3) | Analysis of 7,042 cancers lead to more than 20 distinct mutational signatures | (18) |
| SBS3 signature observed in breast, ovarian and pancreatic tumors showed association with BRA1/2 mutations | ||
| SBS3 is characterized by large deletions (up to 50 bp) with overlapping microhomology at breakpoint junctions | ||
| HRD gene signature | Based on transcriptional profiling approach to systematically identify common molecular changes associated with defective HR repair | (29) |
| Tested on isogenic cell lines established from MCF-10A cells, an immortal human mammary epithelial cell line of nonmalignant origin, with induced deficiency individually in HR repair genes: BRCA1, RAD51 and BRIT1 and other | ||
| HRD gene signature allows interrogation of the status of HR repair by simultaneously considering hundreds of genes and thereby allows identification of HR deficiency in a given cellular state independent of underlying mechanism | ||
| Waddell structural variations load subtyping | Based on whole genome sequencing (WGS) and copy number variation (CNV) analysis of 100 pancreatic ductal adenocarcinomas (PDAC) tumors | (30) |
| Patterns of chromosomal structural variations/rearrangements classified PDACs into 4 subtypes with potential clinical utility: stable, locally rearranged, scattered and unstable | ||
| Genomic instability co-segregated with inactivation of DNA maintenance genes (BRCA1, BRCA2 or PALB2) and a mutational signature of DNA damage repair deficiency | ||
| Double strand break repair signature (DSBR) | Based on whole genome & RNA sequencing on 160 PDAC cases from 154 patients in the discovery cohort and WGS of 95 samples in the replication cohort | (25) |
| Analyses of mutational signatures based on Alexandrov approach identified 4 PDAC principal subtypes: (I) an age-related group dominated by signatures 1 and 5, (II) a double-strand break repair (DSBR) group characterized by signature 3, attributed to deficiencies in homologous recombination repair (HRR) of double-strand breaks; (III) a mismatch repair (MMR) group characterized by signatures 6, 20, and 26, attributed to defects in DNA MMR; and (4) a group characterized by signature 8, of unknown etiology | ||
| DSBR &MMR subtypes were associated with increased expression of antitumor immunity, including activation of CD8-positive T lymphocytes and overexpression of regulatory molecules (CTL4), corresponding to higher frequency of somatic mutations and tumor-specific neoantigens | ||
| HRDetect score | Based on lasso logistic regression model to identify six distinguishing mutational signatures predictive of BRCA1/BRCA2 deficiency | (31) |
| Tested in 560 individuals with breast cancer and validated on independent cohorts of breast, ovarian and pancreatic cancers | ||
| Shows high sensitivity (98.7%) in identification of BRCA1/2 deficient tumors |