Kornelia Neveling,1,2,6 Tuomo Mantere,1,3,4,6 Susan Vermeulen,1 Michiel Oorsprong,1 Ronald van Beek,1
Ellen Kater-Baats,1 Marc Pauper,1 Guillaume van der Zande,1 Dominique Smeets,1
Daniel Olde Weghuis, 1 Marian J.P.L. Stevens-Kroef,1 and Alexander Hoischen1,3,5
Somatic structural variants (SVs) are important drivers of cancer development and progression. In a diagnostic set-up, especially for
hematological malignancies, the comprehensive analysis of all SVs in a given sample still requires a combination of cytogenetic
techniques, including karyotyping, FISH, and CNV microarrays. We hypothesize that the combination of these classical approaches
could be replaced by optical genome mapping (OGM). Samples from 52 individuals with a clinical diagnosis of a hematological malignancy,
divided into simple (<5 aberrations, n 36) and complex (R5 aberrations, n 16) cases, were processed for OGM, reaching on average :283-fold genome coverage. OGM called a total of 918 high-confidence SVs per sample, of which, on average, 13 were rare and >100 kb. In addition, on average, 73 CNVs were called per sample, of which six were >5 Mb. For the 36 simple cases, all
clinically reported aberrations were detected, including deletions, insertions, inversions, aneuploidies, and translocations. For the 16
complex cases, results were largely concordant between standard-of-care and OGM, but OGM often revealed higher complexity than
previously recognized. Detailed technical comparison with standard-of-care tests showed high analytical validity of OGM, resulting
in a sensitivity of 100% and a positive predictive value of >80%. Importantly, OGM resulted in a more complete assessment than
any previous single test and most likely reported the most accurate underlying genomic architecture (e.g., for complex translocations,
chromoanagenesis, and marker chromosomes). In conclusion, the excellent concordance of OGM with diagnostic standard assays demonstrates its potential to replace classical cytogenetic tests as well as to rapidly map novel leukemia drivers.
