11. Optical genome mapping for chromosomal structural variants analysis in hematological malignancies

Knowledge of copy number (CNVs) and structural variants (SVs) is important for the diagnosis and management of hematological malignancies (HM). In myelodysplastic syndromes (MDS), the number and type of SVs/CNVs are essential for prognostic risk-stratification using R-IPSS. Optical genome mapping (OGM) is a novel, single-platform, cytogenomic technique for genome-wide characterization of all types of CNVs/SVs at a high resolution. In this study, we evaluated the performance of OGM in a series of previously well-characterized 49 hematological malignancies (46 MDS, 1 AML and 2 T-ALL) compared to standard-of-care cytogenetic tests. Ultra-high-molecular-weight-DNA extraction from clinical BM samples was followed by DNA labeling and sequential imaging (Saphyr, Bionano) [median coverage: 300X]. Data extracted from rare variant pipeline was filtered for clinically significant variants using standard criteria. OGM successfully facilitated the detection and detailed characterization of 60/65 clonal aberrations (including copy number gains/losses, inversions, inter/intra-chromosomal translocations, dicentric and complex derivative chromosomes) with concordance rates of >95% with conventional karyotyping and 100% with chromosomal microarray. OGM permitted precise gene-level mapping of clinically informative genes such as TP53, TET2 and KMT2A, voiding the need for multiple confirmatory assays. OGM resolved the add/marker chromosomes, and deciphered the underlying complexity and clonal heterogeneity that were not apparent using standard technologies. Further, OGM uncovered 11 additional clinically significant cryptic aberrations in 8 patients [5q/7q/11q deletions, ABL1/TET2 deletions, der5, 2 novel fusions including t(9;11)]. OGM is a powerful and reliable single-platform cytogenomic tool for high-throughput and accurate detection of clinically important SVs in MDS and other HM.