Unraveling Gene Fusions with Optical Genome Mapping in Hematological Malignancies: The Unexplored Terrain

Abstract

Introduction: The cytogenetic analysis currently relies on a combination of traditional techniques, which are low resolution (karyotyping), targeted and require prior knowledge (Fluorescence in-situ hybridization, FISH), or cannot detect balanced SVs and orientation of duplicated segments of the genome (chromosomal microarrays). As a result, additional clinically relevant information remains intractable with this current standard-of-care (SOC) technique. Importantly, hematologic neoplasms frequently harbor acquired balanced translocations, but the discovery of new gene fusions has not been possible due to the lack of gene-level resolution with karyotyping, and analysis of only recurrent gene fusion with FISH panels. Therefore, this study aimed to assess the burden of translocation and gene fusions in hematological malignancies, which could potentially serve as therapeutic targets, and prognostic markers. Methods: This retrospective study included 59 unique and well-characterized samples that were received in our clinical laboratory for cytogenetic analysis with karyotyping and/or FISH testing. These 59 hematological neoplasms included adult acute myeloid leukemia (AML) (n=18), chronic lymphocytic leukemia (CLL) (n=15), myelodysplastic syndromes (MDS) (n=12), plasma cell myeloma (PCM) (n=6), lymphoma (n=3), myeloproliferative disorders/myeloproliferative neoplasms (MPD/MPN) (n=3), and chronic myeloid leukemia (CML) (n=2). Results: Of the 45 cases classified as simple, 38 cases had both karyotyping and FISH results. Of these 38 simple cases (<4 aberrations), seven were found to have ≥4 aberrations with OGM, while 5 out of 7 cases that had only FISH testing showed ≥4 aberrations with OGM. OGM identified several additional SVs, including 69 translocations and 38 potential gene fusions. In the 14 complex cases, OGM identified several additional SVs, including eight chromoanagenesis events (4 cases), 148 translocations, and 68 potential gene fusions Conclusion: OGM demonstrated its unique ability to detect balanced and unbalanced events in one assay. OGM detected 217 additional translocations and 106 novel putative gene fusions in this study and showed that these tumors harbor a significant translocation/gene-fusion burden. The use of OGM might lead to novel therapeutic targets and better patient management as it delineates the complexity of the genome with high resolution intractable with standard-of-care methods. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal