Optical Genome Mapping Reveals the Complex Genetic Landscape of Myeloma

SIMPLE SUMMARY: Myeloma is a hematological cancer characterized by numerous genetic abnormalities currently identified using fluorescent in situ hybridization (FISH). However, FISH is a targeted method offering a limited view of the genome mainly restricted to chromosomal translocations involving the IGH gene and aberrations of chromosomes 1 and 17. A novel technology called optical genome mapping (OGM) has the potential to overcome these limitations. The goal of our study was to evaluate if OGM could replace FISH as a standard method for detection of these abnormalities. We performed OGM analysis on 20 myeloma patients and found that OGM could detect all the classic abnormalities in myeloma. OGM identified additional abnormalities across the entire genome and provided information on their larger genomic context. To our knowledge, this is the first study to show the potential of OGM to significantly change how we detect and study abnormalities in myeloma in a clinical context. ABSTRACT: Fluorescence in situ hybridization (FISH) on enriched CD138 plasma cells is the standard method for identification of clinically relevant genetic abnormalities in multiple myeloma. However, FISH is a targeted analysis that can be challenging due to the genetic complexity of myeloma. The aim of this study was to evaluate the potential of optical genome mapping (OGM) to detect clinically significant cytogenetic abnormalities in myeloma and to provide larger pangenomic information. OGM and FISH analyses were performed on CD138-purified cells of 20 myeloma patients. OGM successfully detected structural variants (SVs) (IGH and MYC rearrangements), copy number variants (CNVs) (17p/TP53 deletion, 1p deletion and 1q gain/amplification) and aneuploidy (gains of odd-numbered chromosomes, monosomy 13) classically expected with myeloma and led to a 30% increase in prognosis yield at our institution when compared to FISH. Despite challenges in the interpretation of OGM calls for CNV and aneuploidy losses in non-diploid genomes, OGM has the potential to replace FISH as the standard of care analysis in clinical settings and to efficiently change how we identify prognostic and predictive markers for therapies in the future. To our knowledge, this is the first study highlighting the feasibility and clinical utility of OGM in myeloma.