The landscape of kinase fusions in cancer

Abstract

Human cancer genomes harbour a variety of alterations leading to the deregulation of key pathways in tumour cells. The genomic characterization of tumours has uncovered numerous genes recurrently mutated, deleted or amplified, but gene fusions have not been characterized as extensively. Here we develop heuristics for reliably detecting gene fusion events in RNA-seq data and apply them to nearly 7,000 samples from The Cancer Genome Atlas. We thereby are able to discover several novel and recurrent fusions involving kinases. These findings have immediate clinical implications and expand the therapeutic options for cancer patients, as approved or exploratory drugs exist for many of these kinases.

MET in Lung Cancer: Biomarker Selection Based on Scientific Rationale

“…However, the kinase fusion KIF5B-MET has been identified in a case of lung adenocarcinoma, and it is feasible that this translocation event could potentially account for a significant portion of MET-driven oncogenesis (67). This fusion-driven activation of MET is most likely due to constitutive dimerization and is likely to be an actionable target for drug-induced inhibition, similar to other fusions in lung cancer such as those involving ALK, ROS1, and RET (67).…”

Fusion proteins in head and neck neoplasms: Clinical implications, genetics, and future directions for targeting

“…2,4 Interestingly, ALK fusions have also been described in esophageal cancer. 4 Of note, they can be targeted by ALK inhibitors, 4 highlighting the utility of fusions in guiding rational therapy for head and neck neoplasms.…”

“…In the majority of cases, a fusion partner provides dimerization domains that constitutively activate a kinase, thereby contributing to tumor development. 2 Thyroid carcinoma has also been shown to harbor a high percentage (70.3%) of in frame fusions compared to other malignancies. 4 Yoshihara et al found that tumor samples with recurrent in-frame fusion transcripts harbored less frequent gene mutations compared to samples without recurrent in frame fusion transcripts.…”

“…2,4 Although the kinase fusions reported in in thyroid malignancies are numerous, they operate via mechanisms with a common underlying theme. In the majority of cases, a fusion partner provides dimerization domains that constitutively activate a kinase, thereby contributing to tumor development.…”

“…They operate via a myriad of mechanisms, including kinase activation or the deletion of regulatory microRNAs. [1][2] Their clinical relevance is evident in the insight they provide into early tumorigenesis as well as their role in facilitating the development of novel targeted therapies and diagnostic applications.…”