Clinically relevant fusion oncogenes: detection and practical implications

Abstract

Mechanistically, chimeric genes result from DNA rearrangements and include parts of preexisting normal genes combined at the genomic junction site. Some rearranged genes encode pathological proteins with altered molecular functions. Those which can aberrantly promote carcinogenesis are called fusion oncogenes. Their formation is not a rare event in human cancers, and many of them were documented in numerous study reports and in specific databases. They may have various molecular peculiarities like increased stability of an oncogenic part, self-activation of tyrosine kinase receptor moiety, and altered transcriptional regulation activities. Currently, tens of low molecular mass inhibitors are approved in cancers as the drugs targeting receptor tyrosine kinase (RTK) oncogenic fusion proteins, that is, including ALK, ABL, EGFR, FGFR1-3, NTRK1-3, MET, RET, ROS1 moieties. Therein, the presence of the respective RTK fusion in the cancer genome is the diagnostic biomarker for drug prescription. However, identification of such fusion oncogenes is challenging as the breakpoint may arise in multiple sites within the gene, and the exact fusion partner is generally unknown. There is no gold standard method for RTK fusion detection, and many alternative experimental techniques are employed nowadays to solve this issue. Among them, RNA-seq-based methods offer an advantage of unbiased high-throughput analysis of only transcribed RTK fusion genes, and of simultaneous finding both fusion partners in a single RNA-seq read. Here we focus on current knowledge of biology and clinical aspects of RTK fusion genes, related databases, and laboratory detection methods.

Translation into Clinical Practice of the G1-G7 Molecular Subgroup Classification of Glioblastoma: Comprehensive Demographic and Molecular Pathway Profiling

“…Whereas the mechanism of constitutive activation has been studied for the rare GOPC1-ROS1 fusion and includes changes in subcellular localization [21] in addition to the overexpression driven by the GOPC1 promoter shown in this study, the activation of PTPRZ1-MET fusions is yet to be studied, including the putative involvement of mechanisms other than overexpression [35]. Although these fusions are rare in glioblastoma, the incidence in the Combined cohort being 0.5% for ST7-MET and LMNA-NTRK1, 1.1% for PTPRZ1-MET and GOPC-ROS1, and 1.6% for FGFR3 fusions [7], they appear to be targetable alterations that also occur in other solid cancers [36]. Currently, the only FDA-approved personalized treatment for glioblastoma is with Entrectinib/Larotrectinib for tumors with an LMNA-NTRK1 fusion [37].…”

Clinical and Molecular Traits of a Novel SPECC1L-ALK Fusion in a Patient with Advanced Non-Small Cell Lung Cancer

“…In particular, the identification of ALK, ROS1, RET, and NTRK1/2/3 gene rearrangements by the scientific community has given an enormous change in therapeutic perspective for patients suffering from NSCLC in the advanced stage of the disease [17]. These rearrangements, although presenting a low incidence, are in fact the basis of therapeutic strategies with molecularly targeted drugs [18]; therefore, they require particular attention aimed at clarifying their heterogeneity and establishing their effective oncogenic activity [19][20][21].…”

Targeting MET in Non-Small Cell Lung Cancer (NSCLC): A New Old Story?

“…As far as IHC is concerned, the major limit is given by false positivity. Indeed, many cases, identified as IHC positivity, have been demonstrated to be FISH- and NGS negative, suggesting the hypothesis that IHC led to the misleading detection of mutations other than fusions (e.g., amplifications) [ 52 ]. Although RT-PCR is an effective, manageable and available method, to date RNA NGS or combined DNA/RNA NGS is the method of choice for the identification of MET gene fusions [ 53 ].…”