Patterns of genomic loss of heterozygosity predict homologous recombination repair defects in epithelial ovarian cancer

Abstract

Background:Defects in BRCA1, BRCA2, and other members of the homologous recombination pathway have potential therapeutic relevance when used to support agents that introduce or exploit double-stranded DNA breaks. This study examines the association between homologous recombination defects and genomic patterns of loss of heterozygosity (LOH).Methods:Ovarian tumours from two independent data sets were characterised for defects in BRCA1, BRCA2, and RAD51C, and LOH profiles were generated. Publically available data were downloaded for a third independent data set. The same analyses were performed on 57 cancer cell lines.Results:Loss of heterozygosity regions of intermediate size were observed more frequently in tumours with defective BRCA1 or BRCA2 (P=10−11). The homologous recombination deficiency (HRD) score was defined as the number of these regions observed in a tumour sample. The association between HRD score and BRCA deficiency was validated in two independent ovarian cancer data sets (P=10−5 and 10−29), and identified breast and pancreatic cell lines with BRCA defects.Conclusion:The HRD score appears capable of detecting homologous recombination defects regardless of aetiology or mechanism. This score could facilitate the use of PARP inhibitors and platinum in breast, ovarian, and other cancers.

Rucaparib in relapsed, platinum-sensitive high-grade ovarian carcinoma (ARIEL2 Part 1): an international, multicentre, open-label, phase 2 trial

“…Progression-free survival was signifi cantly longer in the BRCA mutant subgroup (HR 0·27, 95% CI 0·16-0·44, p<0·0001) and LOH high subgroup (HR 0·62, 0·42-0·90, p=0·011) than in the LOH low subgroup (fi gure 2A). 12 month progressionfree survival was higher in the BRCA mutant subgroup (50%, 95% CI 33-65) and LOH high subgroup (28%, 18-39) than in the LOH low subgroup (10%, [4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19]. The proportionality of hazards assumption was not violated (appendix pp [4][5]15).…”

“…Other biomarkers for homologous recombination defi ciency have been assessed in previous studies, 4,35,36 for example, through retrospective analysis of BRCA mutations in ovarian carcinoma 21 or prospective identifi cation of homozygous deletions or mutations through next-generation sequencing in prostate cancer. 22 Additionally, the NOVA trial (NCT01847274) prospectively tested a homologous recombination defi ciency-based assay in a trial of niraparib as maintenance therapy in patients with platinum-sensitive ovarian cancer.…”

“…28,29 Mutations detected in tumour tissue were identifi ed as germline or somatic by analysis of genomic DNA from blood by use of the BROCAhomologous recombination sequencing assay (University of Washington, Seattle, WA, USA). 30 For each patient, we used the most recently collected tumour specimen (ie, pretreatment biopsy if available or archival biopsy if not) to classify BRCA mutation, genomic LOH, and methylation status (appendix pp [4][5]. Tumour tissue sequencing analyses were all done at the Foundation Medicine central laboratory (Cambridge, MA, USA).…”

Molecular signatures in breast cancer

“…Great interest has therefore been applied to develop 'biomarkers' of HR deficiency based on the pattern of somatic alterations identified in the tumour genome. These genome-based 'tools' utilise either aCGH or SNP array based genome data [64][65][66][67][68][69][70][71] or more recently whole genome sequencing data [91].…”

PARP inhibitors and stratified treatment of prostate cancer

“…Importantly, this can result from alterations in multiple genes, including those for which the mechanism is currently unknown [13]. An assessment of LOH is used to provide a HRD score which has been shown to be well correlated with HR deficiency [14]. Essentially this provides a functional test of DNA repair capability.…”