RESUMO
Optical genome mapping (OGM) recently has demonstrated the potential to improve genetic diagnostics in acute myeloid leukemia (AML). In this study, OGM was utilized as a tool for the detection of genome-wide structural variants and disease monitoring. A previously unrecognized NUP98::ASH1L fusion was detected in an adult patient with secondary AML. OGM identified the fusion of NUP98 to Absent, Small, or Homeotic-Like Histone Lysine Methyltransferase (ASH1L) as result of a complex structural rearrangement between chromosomes 1 and 11. A pipeline for the measurement of rare structural variants (Rare Variant Pipeline, Bionano Genomics, San Diego, CA, USA) was used for detection. As NUP98 and other fusions are relevant for disease classification, this demonstrates the necessity for methods such as OGM for cytogenetic diagnostics in AML. Furthermore, other structural variants showed discordant variant allele frequencies at different time points over the course of the disease and treatment pressure, indicating clonal evolution. These results support OGM to be a valuable tool for primary diagnostics in AML as well as longitudinal testing for disease monitoring and deepening our understanding of genetically heterogenous diseases.
RESUMO
In acute myeloid leukemia (AML), treatment decisions are currently made according to the risk classification of the European LeukemiaNet (ELN), which is based on genetic alterations. Recently, optical genome mapping (OGM) as a novel method proved to yield a genome-wide and detailed cytogenetic characterization at the time of diagnosis. A young female patient suffered from a rather unexpected aggressive disease course under FLT3 targeted therapy in combination with induction chemotherapy. By applying a "next-generation diagnostic workup" strategy with OGM and whole-exome sequencing (WES), a DDX3X: MLLT10 gene fusion could be detected, otherwise missed by routine diagnostics. Furthermore, several aspects of lineage ambiguity not shown by standard diagnostics were unraveled such as deletions of SUZ12 and ARPP21, as well as T-cell receptor recombination. In summary, the detection of this particular gene fusion DDX3X: MLLT10 in a female AML patient and the findings of lineage ambiguity are potential explanations for the aggressive course of disease. Our study demonstrates that OGM can yield novel clinically significant results, including additional information helpful in disease monitoring and disease biology.
RESUMO
Cytogenetic diagnostics play a crucial role in risk stratification and classification of myeloid malignancies such as acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS), thus influencing treatment decisions. Optical genome mapping (OGM) is a novel whole genome method for the detection of cytogenetic abnormalities. Our study assessed the applicability and practicality of OGM as diagnostic tool in AML and MDS patients. In total, 27 patients with AML or MDS underwent routine diagnostics including classical karyotyping and fluorescence in situ hybridization (FISH) or real-time PCR analysis wherever indicated as well as OGM following a recently established workflow. Methods were compared regarding concordance and content of information. In 93%, OGM was concordant to classical karyotyping and a total of 61 additional variants in a predefined myeloid gene-set could be detected. In 67% of samples the karyotype could be redefined by OGM. OGM offers a whole genome approach to cytogenetic diagnostics in AML and MDS with a high concordance to classical cytogenetics. The method has the potential to enter routine diagnostics as a gold standard for cytogenetic diagnostics widely superseding FISH. Furthermore, OGM can serve as a tool to identify genetic regions of interest and future research regarding tumor biology.
