Gene fusion involving the insulin‐like growth factor 1 receptor in an ALK‐negative inflammatory myofibroblastic tumour

Abstract

Aims Inflammatory myofibroblastic tumour (IMT) is a soft tissue tumour primarily affecting children and young adults. Approximately 50% of IMTs have gene fusions involving the receptor tyrosine kinase (RTK)‐encoding ALK gene, providing a molecular rationale for treating IMT patients with unresectable tumours with tyrosine kinase inhibitors (TKI). However, a subset of IMT instead displays fusions affecting other RTKencoding genes, so far including NTRK3, PDGFRB and ROS1. Also, IMTs with variant RTK fusions may respond well to TKI treatment, but can be dif?cult to identify as they are negative for ALK staining at immunohistochemistry, the standard method for detection of ALK rearrangements. Materials and methods We used RNA‐sequencing to search for alternate fusion events in an ALK‐negative IMT. Results and conclusions We found a novel fusion gene ‐ FN1‐IGF1R. The FN1 gene, encoding ?bronectin, is thought to provide a strong promoter activity for the kinase domain of the RTK insulin‐like growth factor 1 receptor, a mechanism similar to previously described RTK fusions in IMT.

Identification of candidates for driver oncogenes in scirrhous‐type gastric cancer cell lines

“…Kekeeva et al discovered a fusion transcript of IGF1R‐TTC23 in bladder cancer that encodes the amino‐terminal extracellular region of IGF1R fused to TTC23 whose function is yet unknown. Piarulli et al reported on a patient with an ALK‐negative inflammatory myofibroblastic tumor carrying FN1‐IGF1R fusion transcript. Both groups identified IGF1R fusion candidates from RNA‐seq data but did not confirm the corresponding genomic rearrangements nor examine the transforming ability of the protein products.…”

Gene rearrangements in consecutive series of pediatric inflammatory myofibroblastic tumors

“…A subset of IMTs carry translocations in a closely related gene, ROS1 3 . In addition, some IMTs harbor fusions involving other tyrosine kinase encoding genes, e.g., NTRK3, RET, PDGFRb , and IGF1R 2,4‐6 . The detection of these rearrangements is of high clinical value, as it ensures the reliability of morphological IMT diagnosis and provides grounds for therapeutic interventions 7‐9 .…”

“…3 In addition, some IMTs harbor fusions involving other tyrosine kinase encoding genes, e.g., NTRK3, RET, PDGFRb, and IGF1R. 2,[4][5][6] The detection of these rearrangements is of high clinical value, as it ensures the reliability of morphological IMT diagnosis and provides grounds for therapeutic interventions. [7][8][9] Current diagnostic approaches are based on immunohistochemical (IHC) detection of activated kinases, FISH-based analysis of gene rearrangements, and identification of translocations by the next-generation sequencing (NGS).…”

“…Hence, ALK/ROS1 antibody staining, being a nonexpensive procedure compatible with conventional morphological analysis, is potentially helpful in directing subsequent molecular testing. It is important to recognize that even positive results of IHC are not sufficient for IMT characterization: genetic analysis of translocation is important both for validation of IHC results and for the identification of the variant of the gene fusion.There are data suggesting that the type of translocation is associated with the IMT disease course 2,6,18. Therefore, the use of PCR or NGS may add some clinical value to IHC/FISH analysis, given that the latter assays are unable to reveal the gene partner.…”

Inflammatory myofibroblastic tumor arising from soft tissues of extremities harboring a novel CLIP2‐ALK fusion

“…10,11 Genetically, IMT is a heterogeneous disease driven by fusions that affect the receptor tyrosine kinase genes, including ALK, ROS1, NTRK3, RET, 8 PDGFRβ and IGF1R. 12 Among them, ALK gene rearrangements were majorly encountered in 50-60% of IMT cases, and predominately occur in children and young adults. Moreover, the ALK gene also has the largest number of fusion partners.…”