The Use of Optical Genome Mapping for the Detection of Tyrosine Kinase Gene Fusions in Myeloid/Lymphoid Neoplasms

Myeloid/Lymphoid Neoplasms with eosinophilia and involvement of Tyrosine Kinase gene fusions (MLN-TK) is a WHO disease category including a diverse group of malignancies characterised by recurrent genomic rearrangements of tyrosine kinase (TK) genes such as PDGFRA, PDGFRB, FGFR1, JAK2, ETV6 and FLT3. Identification of these TK rearrangements is important for the accurate diagnosis of MLN-TK and allows targeted therapy with TK inhibitors. In this study, we validated the use of optical genome mapping (OGM) retrospectively by analysing 11 samples from 10 cases with suspected or known TK rearrangements, previously analysed by current standard of care (SOC) methodologies, i.e., chromosome banding analysis (CBA), FISH and/or PCR-based techniques. In six abnormal cases, OGM was able to detect the rearrangements previously determined by SOC methods. Furthermore, OGM identified the fusion partner in the JAK2- and PDGFRB-rearranged cases and elucidated the mechanism underlying the BCR::FGFR1 and ETV6::SYK rearrangement. In two cases with a normal karyotype, OGM detected two cryptic FIP1L1::PDGFRA and TNIP1::PDGFRB rearrangements. In the two remaining cases, no abnormalities were detected either by OGM or SOC methods. We demonstrate that OGM is a valid technique for the diagnostic workflow of MLN-TK, able to detect TK rearrangements and to identify unknown TK fusion partners.