Gene Fusions
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Cancers ◽  
2021 ◽  
Vol 13 (20) ◽  
pp. 5038
Daniel Rosas ◽  
Luis E. Raez ◽  
Alessandro Russo ◽  
Christian Rolfo

Oncogenic gene fusions are hybrid genes that result from structural DNA rearrangements, leading to unregulated cell proliferation by different mechanisms in a wide variety of cancer. This has led to the development of directed therapies to antagonize a variety of mechanisms that lead to cell growth or proliferation. Multiple oncogene fusions are currently targeted in lung cancer treatment, such as those involving ALK, RET, NTRK and ROS1 among many others. Neuregulin (NRG) gene fusion has been described in the development of normal tissue as well as in a variety of diseases, such as schizophrenia, Hirschsprung’s disease, atrial fibrillation and, most recently, the development of various types of solid tumors, such as renal, gastric, pancreatic, breast, colorectal and, more recently, lung cancer. The mechanism for this is that the NRG1 chimeric ligand leads to aberrant activation of ERBB2 signaling via PI3K-AKT and MAPK cellular cascades, leading to cell division and proliferation. Details regarding the incidence of these gene rearrangements are lacking. Limited case reports and case series have evaluated their clinicopathologic features and prognostic significance in the lung cancer population. Taking this into account, NRG1 could become a targetable alteration in selected patients. This review highlights how the knowledge of new molecular mechanisms of NRG1 fusion may help in gaining new insights into the molecular status of lung cancer patients and unveil a novel targetable molecular marker.

2021 ◽  
Vol 12 ◽  
Gan You ◽  
Xing Fan ◽  
Huimin Hu ◽  
Tao Jiang ◽  
Clark C. Chen

Malignant gliomas are highly heterogeneous brain tumors in molecular genetic background. Despite the many recent advances in the understanding of this disease, patients with adult high-grade gliomas retain a notoriously poor prognosis. Fusions involving oncogenes have been reported in gliomas and may serve as novel therapeutic targets to date. Understanding the gene fusions and how they regulate oncogenesis and malignant progression will contribute to explore new approaches for personalized treatment. By now, studies on gene fusions in gliomas remain limited. However, some current clinical trials targeting fusion genes have presented exciting preliminary findings. The aim of this review is to summarize all the reported fusion genes in high-grade gliomas so far, discuss the characterization of some of the most popular gene fusions occurring in malignant gliomas, as well as their function in tumorigenesis, and the underlying clinical implication as therapeutic targets.

2021 ◽  
Claire Mallard ◽  
Michael J Johnston ◽  
Anna Bobyn ◽  
Ana Nikolic ◽  
Bob Argiropoulos ◽  

ABSTRACTB-cell acute lymphoblastic leukemia (B-ALL) is often driven by chromosome translocations that result in recurrent and well-studied gene fusions. Currently, fluorescent in-situ hybridization probes are employed to detect candidate translocations in bone marrow samples from B-ALL patients. Recently Hi-C, a sequencing-based technique originally designed to reconstruct the three-dimensional architecture of the nuclear genome, was shown to effectively recognize structural variants. Here, we demonstrate that Hi-C can be used as a genome-wide assay to detect translocations and other structural variants of potential clinical interest. Structural variants were identified in both bone marrow and peripheral blood samples, including an ETV6-RUNX1 translocation present in one pediatric B-ALL patient. Our report provides proof-of-principle that Hi-C could be an effective strategy to globally detect driver structural variants in B-ALL peripheral blood specimens, reducing the need for invasive bone marrow biopsies and candidate-based clinical tests.

PLoS ONE ◽  
2021 ◽  
Vol 16 (10) ◽  
pp. e0258188
John Bartlett ◽  
Yutaka Amemiya ◽  
Heleen Arts ◽  
Jane Bayani ◽  
Barry Eng ◽  

Molecular variants including single nucleotide variants (SNVs), copy number variants (CNVs) and fusions can be detected in the clinical setting using deep targeted sequencing. These assays support low limits of detection using little genomic input material. They are gaining in popularity in clinical laboratories, where sample volumes are limited, and low variant allele fractions may be present. However, data on reproducibility between laboratories is limited. Using a ring study, we evaluated the performance of 7 Ontario laboratories using targeted sequencing panels. All laboratories analysed a series of control and clinical samples for SNVs/CNVs and gene fusions. High concordance was observed across laboratories for measured CNVs and SNVs. Over 97% of SNV calls in clinical samples were detected by all laboratories. Whilst only a single CNV was detected in the clinical samples tested, all laboratories were able to reproducibly report both the variant and copy number. Concordance for information derived from RNA was lower than observed for DNA, due largely to decreased quality metrics associated with the RNA components of the assay, suggesting that the RNA portions of comprehensive NGS assays may be more vulnerable to variations in approach and workflow. Overall the results of this study support the use of the OFA for targeted sequencing for testing of clinical samples and suggest specific internal quality metrics that can be reliable indicators of assay failure. While we believe this evidence can be interpreted to support deep targeted sequencing in general, additional studies should be performed to confirm this.

Mengnan Li ◽  
Zhou An ◽  
Qiusu Tang ◽  
Yutong Ma ◽  
Junrong Yan ◽  

2021 ◽  
Adam Grant ◽  
Rosa M. Xicola ◽  
Vivian T. Nguyen ◽  
James Lim ◽  
Curtis Thorne ◽  

Background: The tumor suppressor gene adenomatous polyposis coli (APC) is the initiating mutation in approximately 80% of all colorectal cancers (CRC), underscoring the importance of aberrant regulation of intracellular WNT signaling in CRC development. Recent studies have found that early-onset CRC exhibits an increased proportion of tumors lacking an APC mutation. We set out to identify mechanisms underlying APC mutation-negative (APCmut-) CRCs. Methods: We analyzed data from The Cancer Genome Atlas to compare clinical phenotypes, somatic mutations, copy number variations, gene fusions, RNA expression, and DNA methylation profiles between APCmut- and APC mutation-positive (APCmut+) microsatellite stable CRCs. Results: Transcriptionally, APCmut- CRCs clustered into two approximately equal groups. Cluster One was associated with enhanced mitochondrial activation. Cluster Two was strikingly associated with genetic inactivation or decreased RNA expression of the WNT antagonist RNF43, increased expression of the WNT agonist RSPO3, activating mutation of BRAF, or increased methylation and decreased expression of AXIN2. APCmut- CRCs exhibited evidence of increased immune cell infiltration, with significant correlation between M2 macrophages and RSPO3. Conclusions: APCmut- CRCs comprise two groups of tumors characterized by enhanced mitochondrial activation or increased sensitivity to extracellular WNT, suggesting that they could be respectively susceptible to inhibition of these pathways.

2021 ◽  
Zhengwang Sun ◽  
Qiyue Xu ◽  
Quan Huang ◽  
Mengchen Yin ◽  
Hongqiang Zhang ◽  

Abstract Background: Synovial sarcoma (SS) is a rare and aggressive cancer that can come from distinct soft tissue types including muscle and ligaments. The SS transcriptome is crucial for understanding the SS biology; however, the transcriptomic landscape of SS is still poorly understood. Methods: We performed deep total RNA sequencing on ten paired SS and tumor-adjacent tissues to systematically dissect the transcriptomic profile of SS in terms of gene expression, alternative splicing, gene fusion, and circular RNAs.Results: A total of 2,309 upregulated and downregulated genes were identified between SS and tumor-adjacent tissues. Those upregulated genes could lead to the upregulation of the cell cycle, ribosome, and DNA replication pathways, while the downregulated genes may result in the downregulation of a set of metabolic biological processes and signaling pathways. Moreover, 2,511 genes (including 21 splicing factors) were differentially alternative spliced, indicating that the deregulation of alternative splicing could be one important factor that contributes to the tumorigenesis. Additionally, we identified the known gene fusions of SS18-SSX1/SSX2 as well as 11 potentially novel gene fusions. Interestingly, 49 circular RNAs were differentially expressed and their parental genes could function in muscle contraction and muscle system processes. Conclusions: Collectively, our comprehensive dissection of the transcriptomic profile of SS from both transcriptional and post-transcriptional levels provides novel insights into the biology and underlying molecular mechanism of SS.

2021 ◽  
Pasquale Pisapia ◽  
Francesco Pepe ◽  
Roberta Sgariglia ◽  
Mariantonia Nacchio ◽  
Gianluca Russo ◽  

Although gene fusions occur rarely in non-small-cell lung cancer (NSCLC) patients, they represent a relevant target in treatment decision algorithms. To date, immunohistochemistry and fluorescence in situ hybridization are the two principal methods used in clinical trials. However, using these methods in routine clinical practice is often impractical and time consuming because they can only analyze single genes and the quantity of tissue material is often insufficient. Thus, novel technologies, able to test multiple genes in a single run with minimal sample input, are being under investigation. Here, we discuss the utility of next-generation sequencing and nCounter technologies in detecting simultaneous gene fusions in NSCLC patients.

2021 ◽  
Vol 5 (1) ◽  
Binghao Li ◽  
Hao Qu ◽  
Jing Zhang ◽  
Weibo Pan ◽  
Meng Liu ◽  

AbstractKinase fusions represent an important type of somatic alterations that promote oncogenesis and serve as diagnostic markers in lung cancer. We aimed to identify the landscape of clinically relevant kinase fusions in Chinese lung cancer and to explore rare kinase rearrangements; thus, providing valuable evidence for therapeutic decision making. We performed genomic profiling of 425 cancer-relevant genes from tumor/plasma biopsies from a total of 17,442 Chinese lung cancer patients using next generation sequencing (NGS). Patients’ clinical characteristics and treatment histories were retrospectively studied. A total of 1162 patients (6.66%; 1162/17,442) were identified as having kinase fusions, including 906 adenocarcinomas (ADCs) and 35 squamous cell carcinomas (SCCs). In ADC, 170 unique gene fusion pairs were observed, including rare kinase fusions, SLC12A2-ROS1, NCOA4-RET, and ANK3-RET. As for SCC, 15 unique gene fusions were identified, among which the most frequent were EML4-ALK and FGFR3-TACC3. Analyses of oncogenic mutations revealed a dual role for the gene fusions, CCDC6-RET and FGFR3-TACC3, in driving oncogenesis or serving as acquired resistance mechanisms to kinase inhibitors. In addition, our real-world evidence showed that patients with recurrent kinase fusions with low frequency (two occurrences) could benefit from treatment with kinase inhibitors’ off-label use. Notably, patients with stage IV ADC who had novel RORB-ALK or AFF2-RET fusions, but no other known oncogenic driver mutations, demonstrated favorable clinical outcomes on tyrosine kinase inhibitors. Our data provide a comprehensive overview of the landscape of oncogenic kinase fusions in lung cancer, which assist in recognizing potentially druggable fusions that can be translated into therapeutic applications.

2021 ◽  
Vol 5 (1) ◽  
Michael Bitzer ◽  
Stephan Spahn ◽  
Sepideh Babaei ◽  
Marius Horger ◽  
Stephan Singer ◽  

AbstractIntrahepatic cholangiocarcinoma (iCCA) has emerged as a promising candidate for precision medicine, especially in the case of activating FGFR2 gene fusions. In addition to fusions, a considerable fraction of iCCA patients reveals FGFR2 mutations, which might lead to uncontrolled activation of the FGFR2 pathway but are mostly of unknown functional significance. A current challenge for molecular tumor boards (MTB) is to predict the functional consequences of such FGFR2 alterations to guide potential treatment decisions. We report two iCCA patients with extracellular and juxtamembrane FGFR2 mutations. After in silico investigation of the alterations and identification of activated FGFR2 downstream targets in tumor specimens by immunohistochemistry and transcriptome analysis, the MTB recommended treatment with an FGFR-inhibiting tyrosine kinase inhibitor. Both patients developed a rapidly detectable and prolonged partial response to treatment. These two cases suggest an approach to characterize further detected FGFR2 mutations in iCCA to enable patients´ selection for a successful application of the FGFR -inhibiting drugs.

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