Optical Genome Mapping in MDS and AML as tool for structural variant profiling—comment and data update on Yang et al.: “High-resolution structural variant profiling of myelodysplastic syndromes by optical genome mapping uncovers cryptic aberrations of prognostic and therapeutic significance”

Abstract

Yang et al. recently published their work entitled "High-resolution structural variant profiling of myelodysplastic syndromes by optical genome mapping uncovers cryptic aberrations of prognostic and therapeutic significance" in leukemia [1]. The authors describe a high concordance in 96/99 cases of detected structural variants by routine diagnostics, most importantly chromosomal banding analysis (CBA), and optical genome mapping (OGM) as a whole genome method for structural variant profiling (SVP). More importantly, in 34% of the 101 patients included in the analysis, cryptic variants could be clarified and the risk score according to R-IPSS was changed by additional information obtained by OGM in 17% of patients.These results and the approach chosen are well in line with the data published earlier this year by our group [2]. Although focusing on acute myeloid leukemia (AML), we also included a subgroup of six myelodysplastic syndrome (MDS) patients, three of them with excessive blasts I and three with excessive blasts II, or MDS/AML according to the recently updated international consensus classification [3]. Furthermore, 8 of 21 AML patients had myelodysplasia-related changes.Currently, and updating our previous data, our cohort consists of 42 patients (35 AML and 7 MDS, Table 1). Of 42 patients, a conventional diagnostic approach by cytogenetics (CBA; fluorescence in situ hybridization (FISH) and Copy-number variation (CNV)-microarrays where indicated) was able to detect variants in 26 cases. All but three of these variants could also be seen by OGM, the latter below the applied threshold of 5% variant allele frequency (VAF) and in high-repetitive regions such as around telomers and centromeres [4]. In 27 cases (64%), we could clarify or add additional information by using OGM as a non-DNA dependent amplification based whole genome method. For MDS patients this number was similar with 4/7 cases, where the karyotype could be redefined by utilizing OGM (Table 2).Based on these data, we recently proposed a next-generation work up applying targeted sequencing and a cytogenomics or

Optical Genome Mapping for Cytogenetic Diagnostics in AML

“…We addressed this need by implementing OGM in parallel with our routine diagnostics in AML and MDS. So far, 35 AML and 7 MDS patients have been analyzed at our hematological tertiary center [ 27 , 28 ]. The median age of our study population was 61 years with 59% male patients.…”

“…In our study with 42 patients, 7 were diagnosed with MDS. In these cases, concordance was demonstrated in 83%, with additional information added in 50% of cases [ 27 , 28 ].…”

“… Schematic Graphical illustration of standard cytogenetic methods and OGM based on the data of Gerding et al and Vangala et al (quantitatively inaccurate) [ 27 , 28 ]. The vast majority of variants detected by conventional methods are visible by OGM, which, furthermore, enables the detection of a wider range of aberrations, i.e., novel variants, not visible by other techniques.…”

Novel NUP98::ASH1L Gene Fusion in Acute Myeloid Leukemia Detected by Optical Genome Mapping

“…At our tertiary care center, OGM has been implemented in parallel to routine clinical cytogenetic testing to evaluate its feasibility in acute leukemias, as described previously [23,28,30,31]. Written and informed consent was provided for patient participation in this study and for publication.…”

“…Optical genome mapping (OGM) as a novel genomewide amplification-free technique based on mapping of motif-labeled DNA molecules recently showed a high concordance with current standard genetic diagnostics in different hematologic malignancies, such as AML or MDS. Using high molecular weight DNA isolated from bone marrow aspirate and peripheral blood samples, the methodology was able to identify additional prognostic information, including NUP98::NSD1 and, in one case, the rare fusion NUP98::TNRC18 [22][23][24][25][26][27][28][29].…”