Optical genome mapping refines diagnosis of high-grade myeloid neoplasms through detection of MECOM rearrangements cryptic to conventional karyotype.

MECOM rearrangements (MECOM-r) are high-risk events in myeloid neoplasms often cryptic or incompletely characterized by conventional karyotype analysis. We used optical genome mapping (OGM) to define the frequency and spectrum of MECOM-r in an unselected, consecutively collected cohort of individuals with high-grade myeloid neoplasms (HGMNs) and compared these findings with standard cytogenetic approaches. A total of 252 HGMN specimens, including 224 with definitive diagnoses of acute myeloid leukemia, were processed over a 2-year period using OGM, G-banded karyotyping and, in some cases, reflex fluorescence in situ hybridization (FISH) for the MECOM locus. Cases were retrospectively reviewed to determine whether the identification of MECOM-r by OGM refined diagnosis and/or prognosis. Our diagnostic workflow identified MECOM-r in 12 cases (4.7%), only 6 of which were identified by combined karyotype and FISH analyses, the latter for suspected chromosome 3 abnormalities. The remaining 6 cases were cryptic due to normal karyotypes, highly complex karyotypes lacking apparent chromosome 3 involvement, or culture failure and thus were identified by OGM and reflex FISH. Furthermore, OGM clarified complex architectures, resolved genetic alterations, and identified diverse partner loci, including GATA2, THADA, MYC, PHACTR1, MB21D2, XR_001744423.2, IL12A-AS1, TRIM59, CDK6, and MSI2. Detection of these structural alterations prompted diagnostic and/or risk reclassification in 5 cases. Optical genome mapping doubled the detection rate and improved the structural resolution of MECOM-r by identifying rearrangements incompletely resolved or missed by conventional cytogenetics. Implementation of OGM showed that MECOM-r can be cryptic and frequently overlooked, highlighting the value of high-resolution testing in HGMNs.