Optical Genome Mapping for detecting Homologous Recombination Deficiency (HRD) in human breast cancers

Homologous recombination deficiency (HRD) leads to genomic instability that marks HRD tumor genome with a specific genomic scar. Present in many cancers, HRD is important to be detected as it is associated with a hyper-sensitivity to some classes of drugs, in particular the PARP inhibitors. Here, we investigate the use of structural variants detected by the Optical Genome Mapping (OGM) technology to identify HRD tumors. We first compared the performance of OGM and whole genome sequencing (WGS) in an HRD triple negative breast carcinoma (TNBC) carrying a germline BRCA2 deleterious mutation. We showed the excellent performance of OGM and its ability to recognize subclonal events not detected by WGS. We then analyzed by RVA OGM data from fifteen TNBC samples from the clinical trial RadioPARP. We defined two features characteristic of HRD. Tandem duplication (TD) and insertion events were found increased in HRD tumors. We showed that insertion calls were probably mostly TD too small to be called as TD by RVA. The insertion/TD feature fully discriminated HRD from all homologous recombination proficient (HRP) TNBC but one. This outlier carried a CCNE1 amplicon probably explaining the excess of insertion/TD. Total numbers of translocations were similar in HRP and HRD TNBC. We suggested a novel feature, translocations and intra-fusions isolated from another event by 3 megabases. Isolated translocations and intra-fusions perfectly discriminated HRD from HRP TNBC. Our results demonstrate that the OGM technology is an affordable way of getting an insight of the structural variants present in solid tumors, even with low tumoral cellularity. It represents an alternative technology for HRD diagnosis, which should now be evaluated in independent series of tumors of different tissue origins.