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Developmental Biology Jul 2021YAP1 is a transcriptional co-activator whose activity is controlled by the Hippo signaling pathway. In addition to important functions in normal tissue homeostasis and... (Review)
Review
YAP1 is a transcriptional co-activator whose activity is controlled by the Hippo signaling pathway. In addition to important functions in normal tissue homeostasis and regeneration, YAP1 has also prominent functions in cancer initiation, aggressiveness, metastasis, and therapy resistance. In this review we are discussing the molecular functions of YAP1 and its roles in cancer, with a focus on the different mechanisms of de-regulation of YAP1 activity in human cancers, including inactivation of upstream Hippo pathway tumor suppressors, regulation by intersecting pathways, miRNAs, and viral oncogenes. We are also discussing new findings on the function and biology of the recently identified family of YAP1 gene fusions, that constitute a new type of activating mutation of YAP1 and that are the likely oncogenic drivers in several subtypes of human cancers. Lastly, we also discuss different strategies of therapeutic inhibition of YAP1 functions.
Topics: Adaptor Proteins, Signal Transducing; Animals; Drug Resistance, Neoplasm; Gene Expression Regulation, Neoplastic; Humans; Neoplasms; Oncogene Proteins, Fusion; Oncogenes; Phosphoproteins; Protein Serine-Threonine Kinases; Signal Transduction; Transcription Factors; YAP-Signaling Proteins
PubMed: 33428889
DOI: 10.1016/j.ydbio.2020.12.018 -
Annals of Oncology : Official Journal... Nov 2019Due to the efficacy of tropomyosin receptor kinase (TRK) inhibitor therapy and the recent Food and Drug Administration approval of larotrectinib, it is now clinically... (Review)
Review
Due to the efficacy of tropomyosin receptor kinase (TRK) inhibitor therapy and the recent Food and Drug Administration approval of larotrectinib, it is now clinically important to accurately and efficiently identify patients with neurotrophic TRK (NTRK) fusion-driven cancer. These oncogenic fusions occur when the kinase domain of NTRK1, NTRK2 or NTRK3 fuse with any of a number of N-terminal partners. NTRK fusions are characteristic of a few rare types of cancer, such as secretory carcinoma of the breast or salivary gland and infantile fibrosarcoma, but they are also infrequently seen in some common cancers, such as melanoma, glioma and carcinomas of the thyroid, lung and colon. There are multiple methods for identifying NTRK fusions, including pan-TRK immunohistochemistry, fluorescence in situ hybridisation and sequencing methods, and the advantages and drawbacks of each are reviewed here. While testing algorithms will obviously depend on availability of various testing modalities and economic considerations for each individual laboratory, we propose triaging specimens based on histology and other molecular findings to most efficiently identify tumours harbouring these treatable oncogenic fusions.
Topics: Gene Fusion; Humans; Membrane Glycoproteins; Neoplasms; Oncogene Proteins, Fusion; Receptor Protein-Tyrosine Kinases; Receptor, trkA; Receptor, trkB; Receptor, trkC
PubMed: 31738428
DOI: 10.1093/annonc/mdz384 -
Modern Pathology : An Official Journal... Jan 2019Targeted inhibitors of neurotropic tyrosine kinases are highly effective in selected patients with gene fusions involving NTRK1, NTRK2, or NTRK3. These fusions are...
Targeted inhibitors of neurotropic tyrosine kinases are highly effective in selected patients with gene fusions involving NTRK1, NTRK2, or NTRK3. These fusions are consistently detected in rare cancer types (e.g., secretory breast carcinoma and congenital infantile fibrosarcoma), but the occurrence of NTRK fusions in common cancers and their relationship to other therapy biomarkers are largely unexplored. Tissue samples from 11,502 patients were analyzed for 53 gene fusions and sequencing of 592 genes, along with an immunohistochemical evaluation of TrkA/B/C and PD-L1. Thirty-one cases (0.27% of the entire cohort) had NTRK fusions. The most common fusions were ETV6:NTRK3 (n = 10) and TPM3:NTRK1 (n = 6). Gliomas had the highest number of NTRK fusions (14/982, 1.4%), most commonly involving NTRK2 (n = 9). Seventeen non-glioma cases with NTRK fusions included carcinomas of the lungs, thyroid, breast, cervix, colon, nasal cavity, cancer of unknown primary and soft tissue sarcomas. Strong and uniform Trk expression detected with a pan-Trk immunohistochemistry characterized 7/8 NTRK1 fusion cases and 8/9 NTRK2 fusion cases, while NTRK3 fused cases were positive in 6/11 (55%) of cases. 29% of NTRK fusion cases had no other pathogenic genomic alteration. PD-L1 expression was observed in 23% of NTRK fused cases while high tumor DNA microsatellite instability was detected in two cases. We confirm the rarity of NTRK genes fusions outside the brain malignancies. NTRK inhibitors alone or combined with immune checkpoint inhibitors may be a therapeutic option for a substantial proportion of these patients. Strategies for detection of the NTRK fusion-driven cancers may include immunohistochemistry, but gene fusion detection remains the most reliable tool.
Topics: Adolescent; Adult; Aged; Aged, 80 and over; Child; Discoidin Domain Receptor 2; Female; Humans; Male; Membrane Glycoproteins; Middle Aged; Neoplasms; Oncogene Proteins, Fusion; Receptor, trkA; Receptor, trkB; Young Adult
PubMed: 30171197
DOI: 10.1038/s41379-018-0118-3 -
Journal of Thoracic Oncology : Official... Mar 2021Variable genomic breakpoints have been identified through the application of target-capture DNA next-generation sequencing (NGS) for ALK, ROS1, and RET fusion detection...
INTRODUCTION
Variable genomic breakpoints have been identified through the application of target-capture DNA next-generation sequencing (NGS) for ALK, ROS1, and RET fusion detection in NSCLC. We investigated whether ALK, ROS1, and RET genomic breakpoint location can predict matched targeted therapy efficacy.
METHODS
NSCLCs were analyzed by DNA NGS, target-specific RNA NGS, whole-transcriptome sequencing, and immunohistochemistry.
RESULTS
In total, 3787 NSCLC samples were analyzed. DNA NGS detected ALK, ROS1, and RET fusions in 241, 59, and 76 cases, respectively. These fusions were divided into canonical (single EML4-ALK, CD74/EZR/TPM3/SDC4-ROS1, and KIF5B/CCDC6-RET fusions), noncanonical (single non-EML4-ALK, non-CD74/EZR/TPM3/SDC4-ROS1, and non-KIF5B/CCDC6-RET fusions), and primary/reciprocal (both primary and reciprocal rearrangements were detected) subtypes on the basis of genomic breakpoint position, and noncanonical and primary/reciprocal subtypes were defined as uncommon fusions. Further RNA sequencing and immunohistochemistry revealed that six of 47 (12.8%) uncommon fusions were actually nonproductive rearrangements that generated no aberrant transcripts or proteins. Moreover, genomic breakpoints of canonical ALK and RET, but not ROS1, fusions always predicted breakpoints at the transcript level, whereas 85.4% (35 of 41) of uncommon fusions actually produced canonical fusion transcripts. Patients with uncommon ALK fusion (n = 31) who received first-line crizotinib exhibited shorter median progression-free survival than those with canonical ALK fusion (n = 53, 8.4 mo versus 12.0 mo, p = 0.004). However, no difference in progression-free survival was observed when only ALK RNA or protein-positive cases were analyzed (p = 0.185).
CONCLUSIONS
Uncommon ALK, ROS1, and RET genomic breakpoint is an unreliable predictor of matched targeted therapy efficacy. Functional validation by RNA or protein assay may add value for the accurate detection and interpretation of rare fusions.
Topics: Anaplastic Lymphoma Kinase; Genomics; Humans; Lung Neoplasms; Oncogene Proteins, Fusion; Protein-Tyrosine Kinases; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-ret
PubMed: 33248323
DOI: 10.1016/j.jtho.2020.10.156 -
The American Journal of Managed Care Jan 2022The tropomyosin receptor kinase (TRK) family of proteins is encoded by neurotrophic tyrosine receptor kinase (NTRK) genes and has a role in the development and normal... (Review)
Review
The tropomyosin receptor kinase (TRK) family of proteins is encoded by neurotrophic tyrosine receptor kinase (NTRK) genes and has a role in the development and normal functioning of the nervous system. NTRK gene fusions have been identified as oncogenic drivers in a wide range of tumors in both adult and pediatric patients. There has recently been a paradigm shift in cancer treatment toward biomarker-based targeted therapies, as an increasing number of actionable targets are being identified across different tumors and/or tumor histologies. These targeted agents offer greater comparative effectiveness and safety vs historical nontargeted standard therapies. The development of drugs that specifically target oncogenic drivers of cancer has led to the emergence of screening technologies to identify the patients most likely to benefit from targeted therapy. This review describes the role of NTRK gene fusions in cancer and outlines the epidemiology of NTRK gene fusions, the therapeutic benefits of targeting TRK fusions with small molecule inhibitors, and recommendations for NTRK gene fusion testing in adult and pediatric patients with cancer, in order to guide treatment decisions.
Topics: Adult; Child; Gene Fusion; Humans; Neoplasms; Oncogene Proteins, Fusion; Oncogenes; Protein Kinase Inhibitors; Receptor, trkA
PubMed: 35201680
DOI: 10.37765/ajmc.2022.88834 -
Current Oncology Reports Apr 2023During the past few years there has been an expansion in our understanding of gene fusions and translocations involved in cancer of the sinonasal tract. Here we review... (Review)
Review
PURPOSE OF REVIEW
During the past few years there has been an expansion in our understanding of gene fusions and translocations involved in cancer of the sinonasal tract. Here we review the downstream biologic effects, clinical characteristics, and pathologic features of these tumors. The molecular consequences and neo-antigens resulting from these chromosomal aberrations are considered and targets for current and future clinical trials discussed.
RECENT FINDINGS
Several new, clinically relevant, chromosomal aberrations have been discovered and evaluated to varying degrees in sinonasal tumors including DEK::AFF2, BRD4::NUT, ADCK4::NUMBL, and ETV6::NTRK3. Sinonasal malignancies demonstrate a diverse genetic landscape and varying clinical courses. Recent studies illustrate that gene fusions and translocations may play a role in carcinogenesis in certain sinonasal tumor subtypes and may be used to develop new biomarker-driven and patient-centered treatments.
Topics: Humans; Transcription Factors; Nuclear Proteins; Neoplasms; Translocation, Genetic; Gene Fusion; Oncogene Proteins, Fusion; Poly-ADP-Ribose Binding Proteins; Chromosomal Proteins, Non-Histone; Oncogene Proteins; Cell Cycle Proteins
PubMed: 36753024
DOI: 10.1007/s11912-023-01364-x -
Biochimica Et Biophysica Acta. Gene... Jul 2020Over the last 15 years the Diagnostic Center of Acute Leukemia (DCAL) at the Frankfurt University has diagnosed and elucidated the Mixed Lineage Leukemia (MLL)... (Review)
Review
Over the last 15 years the Diagnostic Center of Acute Leukemia (DCAL) at the Frankfurt University has diagnosed and elucidated the Mixed Lineage Leukemia (MLL) recombinome with >100 MLL fusion partners. When analyzing all these different events, balanced chromosomal translocations were found to comprise the majority of these cases (~70%), while other types of genetic rearrangements (3-way-translocations, spliced fusions, 11q inversions, interstitial deletions or insertion of chromosomal fragments into other chromosomes) account for about 30%. In nearly all those complex cases, functional fusion proteins can be produced by transcription, splicing and translation. With a few exceptions (10 out of 102 fusion genes which were per se out-of-frame), all these genetic rearrangements produced a direct MLL fusion gene, and in 94% of cases an additional reciprocal fusion gene. So far, 114 patients (out of 2454 = ~5%) have been diagnosed only with the reciprocal fusion allele, displaying no MLL-X allele. The fact that so many MLL rearrangements bear at least two fusion alleles, but also our findings that several direct MLL fusions were either out-of-frame fusions or missing, raises the question about the function and importance of reciprocal MLL fusions. Recent findings also demonstrate the presence of reciprocal MLL fusions in sarcoma patients. Here, we want to discuss the role of reciprocal MLL fusion proteins for leukemogenesis and beyond.
Topics: Animals; Chromatin Assembly and Disassembly; Gene Expression Regulation, Neoplastic; Humans; Leukemia, Biphenotypic, Acute; Myeloid-Lymphoid Leukemia Protein; Oncogene Proteins, Fusion
PubMed: 32294539
DOI: 10.1016/j.bbagrm.2020.194547 -
Viruses Nov 2015In the nearly two decades since the popularization of green fluorescent protein (GFP), fluorescent protein-based methodologies have revolutionized molecular and cell... (Review)
Review
In the nearly two decades since the popularization of green fluorescent protein (GFP), fluorescent protein-based methodologies have revolutionized molecular and cell biology, allowing us to literally see biological processes as never before. Naturally, this revolution has extended to virology in general, and to the study of alpha herpesviruses in particular. In this review, we provide a compendium of reported fluorescent protein fusions to herpes simplex virus 1 (HSV-1) and pseudorabies virus (PRV) structural proteins, discuss the underappreciated challenges of fluorescent protein-based approaches in the context of a replicating virus, and describe general strategies and best practices for creating new fluorescent fusions. We compare fluorescent protein methods to alternative approaches, and review two instructive examples of the caveats associated with fluorescent protein fusions, including describing several improved fluorescent capsid fusions in PRV. Finally, we present our future perspectives on the types of powerful experiments these tools now offer.
Topics: Alphaherpesvirinae; Biomedical Research; Host-Pathogen Interactions; Luminescent Proteins; Recombinant Fusion Proteins; Staining and Labeling; Virology
PubMed: 26610544
DOI: 10.3390/v7112915 -
The Journal of Biological Chemistry 2021Within the AGC kinase superfamily, gene fusions resulting from chromosomal rearrangements have been most frequently described for protein kinase C (PKC), with gene...
Within the AGC kinase superfamily, gene fusions resulting from chromosomal rearrangements have been most frequently described for protein kinase C (PKC), with gene fragments encoding either the C-terminal catalytic domain or the N-terminal regulatory moiety fused to other genes. Kinase fusions that eliminate regulatory domains are typically gain of function and often oncogenic. However, several quality control pathways prevent accumulation of aberrant PKC, suggesting that PKC fusions may paradoxically be loss of function. To explore this topic, we used biochemical, cellular, and genome editing approaches to investigate the function of fusions that retain the portion of the gene encoding either the catalytic domain or regulatory domain of PKC. Overexpression studies revealed that PKC catalytic domain fusions were constitutively active but vulnerable to degradation. Genome editing of endogenous genes to generate a cancer-associated PKC fusion resulted in cells with detectable levels of fusion transcript but no detectable protein. Hence, PKC catalytic domain fusions are paradoxically loss of function as a result of their instability, preventing appreciable accumulation of protein in cells. Overexpression of a PKC regulatory domain fusion suppressed both basal and agonist-induced endogenous PKC activity, acting in a dominant-negative manner by competing for diacylglycerol. For both catalytic and regulatory domain fusions, the PKC component of the fusion proteins mediated the effects of the full-length fusions on the parameters examined, suggesting that the partner protein is dispensable in these contexts. 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.
Topics: Animals; Binding Sites; COS Cells; Catalytic Domain; Cell Line, Tumor; Chlorocebus aethiops; Diglycerides; Fluorescence Resonance Energy Transfer; Humans; Loss of Function Mutation; Neoplasms; Phosphorylation; Protein Domains; Protein Kinase C; Protein Kinase C-alpha; Recombinant Fusion Proteins
PubMed: 33617877
DOI: 10.1016/j.jbc.2021.100445 -
Blood Sep 2022Recurrent MEF2D fusions with poor prognosis have been identified in B-cell precursor ALL (BCP-ALL). The molecular mechanisms underlying the pathogenic function of MEF2D...
Recurrent MEF2D fusions with poor prognosis have been identified in B-cell precursor ALL (BCP-ALL). The molecular mechanisms underlying the pathogenic function of MEF2D fusions are poorly understood. Here, we show that MEF2D-HNRNPUL1 (MH) knock-in mice developed a progressive disease from impaired B-cell development at the pre-pro-B stage to pre-leukemia over 10 to 12 months. When cooperating with NRASG12D, MH drove an outbreak of BCP-ALL, with a more aggressive phenotype than the NRASG12D-induced leukemia. RNA-sequencing identified key networks involved in disease mechanisms. In chromatin immunoprecipitation-sequencing experiments, MH acquired increased chromatin-binding ability, mostly through MEF2D-responsive element (MRE) motifs in target genes, compared with wild-type MEF2D. Using X-ray crystallography, the MEF2D-MRE complex was characterized in atomic resolution, whereas disrupting the MH-DNA interaction alleviated the aberrant target gene expression and the B-cell differentiation arrest. The C-terminal moiety (HNRNPUL1 part) of MH was proven to contribute to the fusion protein's trans-regulatory activity, cofactor recruitment, and homodimerization. Furthermore, targeting MH-driven transactivation of the HDAC family by using the histone deacetylase inhibitor panobinostat in combination with chemotherapy improved the overall survival of MH/NRASG12D BCP-ALL mice. Altogether, these results not only highlight MH as an important driver in leukemogenesis but also provoke targeted intervention against BCP-ALL with MEF2D fusions.
Topics: Animals; Chromatin; DNA; Histone Deacetylase Inhibitors; MEF2 Transcription Factors; Mice; Oncogene Proteins, Fusion; Panobinostat; Precursor Cell Lymphoblastic Leukemia-Lymphoma; RNA
PubMed: 35544603
DOI: 10.1182/blood.2022016241