Introduction to Oncogenic Fusion

What is/are Oncogenic Fusion?

Oncogenic Fusion - In all samples of CD30-positive LPD and MF, oncogenic fusions afflicting the JAK/STAT signaling pathway were present, namely NPM1-TYK2 in patient 1 and ILF3-JAK2 in patient 2. ^[1] Purpose: Oncogenic fusions involving the neuregulin 1 (NRG1) gene are found in approximately 0. ^[2] Oncogenic fusions represent compelling druggable targets in solid tumours highlighted by the recent site agnostic FDA approval of larotrectinib for NTRK rearrangements. ^[3] These alterations were detected in 14 patients, three of whom had oncogenic fusions. ^[4] Molecular dysregulation of KAT6A has been observed in several cancers, including amplifications in breast, lung, ovarian cancer along with oncogenic fusions in AML. ^[5] To address this, we have developed in vitro models of oncogenic fusions, in particular, EWSR1-CREB1 and EWSR1-ATF1, in human embryonic stem (hES) cells, which are capable of multipotent differentiation, using CRISPR-Cas9 technology and HDR together with conditional fusion gene expression that allows investigation into the early steps of cellular transformation. ^[6] Two selective histology-agnostic tropomyosin receptor kinase (TRK) inhibitors are currently approved for malignancies with these oncogenic fusions. ^[7] Addition of the oncogenic fusion to the NRAS mutation also results in a higher leukemic stem cell frequency. ^[8] Moreover, this work has broad implications for studies of leukemogenesis applicable to a variety of oncogenic fusion-driven pediatric leukemias, providing a robust and tractable model system to characterize the molecular mechanisms of leukemogenesis and identify biomarkers for disease diagnosis and targets for therapy. ^[9] Lee, and colleagues showed that oncogenic fusions were more commonly associated with invasive disease, increased expression of MAPK signaling pathway genes (ERK score), and decreased expression of the sodium-iodine symporter, which was restored by RET- and NTRK-inhibitory therapy. ^[10] Taken together, our findings reveal that PKC gene fusions are distinct from oncogenic fusions and present a mechanism by which loss of PKC function occurs in cancer. ^[11] Recently, more novel mechanisms, including rare EGFR point mutations and oncogenic fusions, were reported. ^[12] The latter were enriched for oncogenic fusions, with 11 non-recurrent fusion transcripts, including two previously undescribed fusions, STRN-RET and TG-PBF. ^[13] The presence of oncogenic fusions including NTRK fusions are rare but important to identify. ^[14] The molecular profile of CSM may reveal EWSR1 or FUS gene rearrangement, but as we showcase, the diagnosis remains possible in the absence of this oncogenic fusion. ^[15] Oncogenic fusions involving NTRK1, NTRK2, and NTRK3 with various partners are diagnostic of infantile fibrosarcoma and secretory carcinoma yet also occur in lower frequencies across many types of malignancies. ^[16] On the other hand, a variety of ALK gene alterations, such as oncogenic fusion, activating point mutation, or wild type gene amplification, have been recently discovered as the powerful oncogene in various tumors, and these ALK mutations have also been known as the potential therapeutic targets against tumors harboring these ALK mutations. ^[17] Oncogenic fusions of FGFR1 with various fusion partners were described in myeloid proliferative neoplasms, and overexpression and mutations of FGFR3 are common in multiple myeloma. ^[18] Chromoplexy has also been described as a mechanism of resistance, where multiple closed chain rearrangements cause loss-of-function of tumor suppressor genes and gain-in-function of oncogenic fusions. ^[19] To the editor, Chromosomal translocations leading to oncogenic fusions are increasingly being recognized as molecular drivers of gliomas [9]. ^[20] Oncogenic fusions are rare in colorectal carcinomas, but may be important for prognosis and therapy. ^[21] In contrast to the tumor-specific gene-rearrangement-positive acute lymphoblastic leukemia (ALL) and the oncogenic fusion-gene-positive chronic myelogenous leukemia (CML) and several solid tumors, the clinical significance of MRD remains to be established in neuroblastoma. ^[22] The detection of oncogenic fusions can be conducted using fluorescence in situ hybridization, reverse-transcription polymerase chain reaction, immunohistochemistry, or NGS. ^[23] 50% (137/275) have structural alterations in their tumors with over half of these (74/137) harboring an oncogenic fusion that is the main, or only identified, driver of the cancer. ^[24]

protein nucleophosmin anaplastic

BACKGROUND Inhibitors for signal transducer and activator of transcription 3 (STAT3), Stattic, BP-1-102, and LLL12 significantly induce apoptosis in transformed Ba/F3 cells expressing an oncogenic fusion protein, nucleophosmin-anaplastic lymphoma kinase (NPM-ALK) that induces the activation of STAT3. ^[1] BACKGROUND Inhibitors for signal transducer and activator of transcription 3 (STAT3), Stattic, BP-1-102, and LLL12 significantly induce apoptosis in transformed Ba/F3 cells expressing an oncogenic fusion protein, nucleophosmin-anaplastic lymphoma kinase (NPM-ALK) that induces the activation of STAT3. ^[2] Anaplastic large cell lymphoma (ALCL) is associated with a characteristic chromosomal translocation that generates the oncogenic fusion protein, nucleophosmin-anaplastic lymphoma kinase (NPM-ALK). ^[3]

non small cell

Building an effective concordance study: Plasma Next Generation Sequencing (NGS) for oncogenic fusion detection in non-small cell lung carcinoma (NSCLC) [abstract]. ^[1] Introduction ROS1 oncogenic fusion, which was first identified by Rikova et al, is reported to be present in 1%–2% of non-small cell lung cancers (NSCLCs) and is defined as a distinct molecular sub-group. ^[2]

anaplastic lymphoma kinase

Chromosomal translocation resulting in the fusion between the echinoderm microtubule-associated protein-like 4 ( EML4 ) gene and the anaplastic lymphoma kinase ( ALK ) gene has been considered as a novel oncogenic fusion in a subset of non-small cell lung cancer ( NSCLC ), mostly in non-smokers with adenocarcinoma. ^[1]

Novel Oncogenic Fusion

The development of sequencing techniques, such as RNA-Sequencing, has identified many gene rearrangements encoding novel oncogenic fusions. ^[1] In each case, POG analyses identified genomic drivers including novel oncogenic fusions, aberrant pathways, and putative therapeutic targets. ^[2] We demonstrate that RNA-seq is a powerful tool to identify clinically relevant and histology-specific recurrent mutations, novel oncogenic fusions, and translationally relevant immunogenomic patterns for pediatric cancers. ^[3] Chromosomal translocation resulting in the fusion between the echinoderm microtubule-associated protein-like 4 ( EML4 ) gene and the anaplastic lymphoma kinase ( ALK ) gene has been considered as a novel oncogenic fusion in a subset of non-small cell lung cancer ( NSCLC ), mostly in non-smokers with adenocarcinoma. ^[4]

These Oncogenic Fusion

These oncogenic fusion proteins are tumor-specific, and, therefore, constitute an exceptional target. ^[1] These oncogenic fusions occur when the kinase domain of NTRK1, NTRK2 or NTRK3 fuse with any of a number of N-terminal partners. ^[2] These oncogenic fusions occur when the kinase domain of NTRK1, NTRK2 or NTRK3 fuse with any of a number of N-terminal partners. ^[3]

Tacc3 Oncogenic Fusion

We found that pan-FGFR inhibitors and MEK1/2 inhibitors antagonized the PPARG-driven reporter assay with potency similar to reported values for their cognate targets (1-20 nM) and interestingly, RT112 cells carry an FGFR3-TACC3 oncogenic fusion. ^[1] Molecular testing was performed and revealed a TERT promotor mutation, an FGFR3-TACC3 oncogenic fusion, and a copy number loss in CDKN2A/CDKN2B. ^[2]

Alk Oncogenic Fusion

Anaplastic large cell lymphoma (ALCL) is an aggressive type of Non-Hodgkin Lymphoma, characterized by expression of the NPM/ALK oncogenic fusion tyrosine kinase. ^[1] The most frequent rearrangement, the EML4-ALK oncogenic fusion, has more than 10 distinct variants, each with a discrete breakpoint in EML4. ^[2]

Functional Oncogenic Fusion

Despite the important role of the PI3K/AKT/mTOR axis in the pathogenesis of cancer, to date there have been few functional oncogenic fusions identified involving the AKT genes. ^[1] The MLL and AF9 bcrs are sensitive to these agents and recombinogenic independent of their native context suggesting bcr sequences themselves are drivers of illegitimate DNA repair reactions and translocations, not generation of functional oncogenic fusions. ^[2]

Specific Oncogenic Fusion

A subtype of AML, acute promyelocytic leukemia (APL), is mainly driven by a specific oncogenic fusion event of promyelocytic leukemia-RA receptor fusion oncoprotein (PML-RARα). ^[1] In-depth studies on the transfection mechanism revealed that transfection efficiency in K-562 cells does not depend on the specific oncogenic fusion gene BCR-ABL alone. ^[2]

Harboring Oncogenic Fusion

Background Colorectal carcinoma (CRC) harboring oncogenic fusions has been reported to be highly enriched in mismatch repair deficient (dMMR) tumors with MLH1 hypermethylation ( MLH1 me+ ) and wild-type BRAF and RAS. ^[1] Background: Colorectal carcinoma (CRC) harboring oncogenic fusions has been reported to be highly enriched in mismatch repair deficient (dMMR) tumors with MLH1 hypermethylation (MLH1me+) and wild-type BRAF and RAS. ^[2]

Targetable Oncogenic Fusion

In children with inoperable ALK-negative IMTs, molecular testing must be performed to identify other targetable oncogenic fusions, including TFG-ROS1. ^[1] One such mechanism is the emergence of acquired, targetable oncogenic fusion events. ^[2]

oncogenic fusion protein

Similar PLD-driven co-condensation of mSWI/SNF with transcription factors can be employed by other oncogenic fusion proteins with a generic PLD-DBD domain architecture for global transcriptional reprogramming. ^[1] In Ewing sarcoma research, ChIP-seq provided important insights into the mechanism of action of the major oncogenic fusion protein EWSR1-FLI1 and related epigenetic and transcriptional changes. ^[2] As the majority of AML events are associated with chromosomal translocation resulting in oncogenic fusion proteins, it is valuable to comprehensively understand the mutual interactions between HDACs and oncogenic proteins. ^[3] Similar PLD‐driven co‐condensation of mSWI/SNF with transcription factors can be employed by other oncogenic fusion proteins with a generic PLD‐DBD domain architecture for global transcriptional reprogramming. ^[4] We focus on Ewing Sarcoma, a pediatric cancer driven by a single oncogenic fusion protein EWSR1-FLI1, and with little to no additional somatic mutations, making it a prototypical form of cancer whose adaptation to microenvironments is likely driven by acute, non-genomic mechanisms. ^[5] Endometrial stromal sarcoma (ESS) is the