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Genome Biology Jan 2016RNA-sequencing (RNA-seq) has a wide variety of applications, but no single analysis pipeline can be used in all cases. We review all of the major steps in RNA-seq data... (Review)
Review
RNA-sequencing (RNA-seq) has a wide variety of applications, but no single analysis pipeline can be used in all cases. We review all of the major steps in RNA-seq data analysis, including experimental design, quality control, read alignment, quantification of gene and transcript levels, visualization, differential gene expression, alternative splicing, functional analysis, gene fusion detection and eQTL mapping. We highlight the challenges associated with each step. We discuss the analysis of small RNAs and the integration of RNA-seq with other functional genomics techniques. Finally, we discuss the outlook for novel technologies that are changing the state of the art in transcriptomics.
Topics: Alternative Splicing; Base Sequence; Gene Expression Profiling; Gene Fusion; Genomics; High-Throughput Nucleotide Sequencing; RNA; Sequence Analysis, RNA; Software
PubMed: 26813401
DOI: 10.1186/s13059-016-0881-8 -
International Journal of Molecular... Aug 2022Oncogenic fusion genes have emerged as successful targets in several malignancies, such as chronic myeloid leukemia and lung cancer. Fusion of the fibroblast growth... (Review)
Review
Oncogenic fusion genes have emerged as successful targets in several malignancies, such as chronic myeloid leukemia and lung cancer. Fusion of the fibroblast growth receptor 3 and the transforming acidic coiled coil containing protein-FGFR3-TACC3 fusion-is prevalent in 3-4% of human glioblastoma. The fusion protein leads to the constitutively activated kinase signaling of FGFR3 and thereby promotes cell proliferation and tumor progression. The subgroup of FGFR3-TACC3 fusion-positive glioblastomas presents with recurrent clinical and histomolecular characteristics, defining a distinctive subtype of IDH-wildtype glioblastoma. This review aims to provide an overview of the available literature on FGFR3-TACC3 fusions in glioblastoma and possible implications for actual clinical practice.
Topics: Gene Fusion; Glioblastoma; Humans; Lung Neoplasms; Microtubule-Associated Proteins; Oncogene Fusion; Receptor, Fibroblast Growth Factor, Type 3
PubMed: 35955806
DOI: 10.3390/ijms23158675 -
Oncotarget Aug 2016Fibroblast growth factor receptors (FGFR) are transmembrane kinase proteins with growing importance in cancer biology given the frequency of molecular alterations and... (Review)
Review
Fibroblast growth factor receptors (FGFR) are transmembrane kinase proteins with growing importance in cancer biology given the frequency of molecular alterations and vast interface with multiple other signaling pathways. Furthermore, numerous FGFR inhibitors in clinical development demonstrate the expanding therapeutic relevance of this pathway. Indeed, results from early phase clinical trials already indicate that a subset of patients with advanced tumors derive benefit from FGFR targeted therapies. FGFR gene aberrations and FGFR gene rearrangements are relatively rare in solid malignancies. The recently described FGFR3-TACC3 fusion protein has a constitutively active tyrosine kinase domain and promotes aneuploidy. We summarize the prevalence data on FGFR3-TACC3 fusions among different histological tumor types and the preliminary evidence that this rearrangement represents a targetable molecular aberration in some patients with solid tumors.
Topics: Animals; Gene Fusion; Humans; Microtubule-Associated Proteins; Neoplasms; Receptor, Fibroblast Growth Factor, Type 3; Translocation, Genetic
PubMed: 27409839
DOI: 10.18632/oncotarget.10482 -
Nucleic Acids Research Jan 2018Gene fusion represents a class of molecular aberrations in cancer and has been exploited for therapeutic purposes. In this paper we describe TumorFusions, a data portal...
Gene fusion represents a class of molecular aberrations in cancer and has been exploited for therapeutic purposes. In this paper we describe TumorFusions, a data portal that catalogues 20 731 gene fusions detected in 9966 well characterized cancer samples and 648 normal specimens from The Cancer Genome Atlas (TCGA). The portal spans 33 cancer types in TCGA. Fusion transcripts were identified via a uniform pipeline, including filtering against a list of 3838 transcript fusions detected in a panel of 648 non-neoplastic samples. Fusions were mapped to somatic DNA rearrangements identified using whole genome sequencing data from 561 cancer samples as a means of validation. We observed that 65% of transcript fusions were associated with a chromosomal alteration, which is annotated in the portal. Other features of the portal include links to SNP array-based copy number levels and mutational patterns, exon and transcript level expressions of the partner genes, and a network-based centrality score for prioritizing functional fusions. Our portal aims to be a broadly applicable and user friendly resource for cancer gene annotation and is publicly available at http://www.tumorfusions.org.
Topics: DNA Copy Number Variations; Databases, Genetic; Gene Expression Regulation, Neoplastic; Gene Fusion; Humans; Neoplasms; Oncogene Proteins, Fusion; Polymorphism, Single Nucleotide; Reproducibility of Results; User-Computer Interface; Whole Genome Sequencing
PubMed: 29099951
DOI: 10.1093/nar/gkx1018 -
Nature Communications Sep 2014Human cancer genomes harbour a variety of alterations leading to the deregulation of key pathways in tumour cells. The genomic characterization of tumours has uncovered...
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.
Topics: Gene Expression Profiling; Gene Fusion; Genome, Human; Humans; Molecular Targeted Therapy; Neoplasms; Phosphotransferases; Sequence Analysis, RNA
PubMed: 25204415
DOI: 10.1038/ncomms5846 -
Pediatric Blood & Cancer Apr 2022Children and adolescents with rhabdomyosarcoma (RMS) comprise a heterogeneous population with variable overall survival rates ranging between approximately 6% and 100%... (Review)
Review
Children and adolescents with rhabdomyosarcoma (RMS) comprise a heterogeneous population with variable overall survival rates ranging between approximately 6% and 100% depending on defined risk factors. Although the risk stratification of patients has been refined across five decades of collaborative group studies, molecular prognostic biomarkers beyond FOXO1 fusion status have yet to be incorporated prospectively in upfront risk-based therapy assignments. This review describes the evolution of risk-based therapy and the current risk stratification, defines a new risk stratification incorporating novel biomarkers, and provides the rationale for the current and upcoming Children's Oncology Group RMS studies.
Topics: Adolescent; Child; Gene Fusion; Humans; Rhabdomyosarcoma; Rhabdomyosarcoma, Embryonal; Risk Assessment; Risk Factors
PubMed: 35129294
DOI: 10.1002/pbc.29511 -
Rlf-Mycl Gene Fusion Drives Tumorigenesis and Metastasis in a Mouse Model of Small Cell Lung Cancer.Cancer Discovery Dec 2021Small cell lung cancer (SCLC) has limited therapeutic options and an exceptionally poor prognosis. Understanding the oncogenic drivers of SCLC may help define novel...
UNLABELLED
Small cell lung cancer (SCLC) has limited therapeutic options and an exceptionally poor prognosis. Understanding the oncogenic drivers of SCLC may help define novel therapeutic targets. Recurrent genomic rearrangements have been identified in SCLC, most notably an in-frame gene fusion between RLF and MYCL found in up to 7% of the predominant ASCL1-expressing subtype. To explore the role of this fusion in oncogenesis and tumor progression, we used CRISPR/Cas9 somatic editing to generate a Rlf-Mycl-driven mouse model of SCLC. RLF-MYCL fusion accelerated transformation and proliferation of murine SCLC and increased metastatic dissemination and the diversity of metastatic sites. Tumors from the RLF-MYCL genetically engineered mouse model displayed gene expression similarities with human RLF-MYCL SCLC. Together, our studies support RLF-MYCL as the first demonstrated fusion oncogenic driver in SCLC and provide a new preclinical mouse model for the study of this subtype of SCLC.
SIGNIFICANCE
The biological and therapeutic implications of gene fusions in SCLC, an aggressive metastatic lung cancer, are unknown. Our study investigates the functional significance of the in-frame RLF-MYCL gene fusion by developing a Rlf-Mycl-driven genetically engineered mouse model and defining the impact on tumor growth and metastasis. This article is highlighted in the In This Issue feature, p. 2945.
Topics: Animals; Carcinogenesis; Cell Line, Tumor; Gene Fusion; Genes, myc; Lung Neoplasms; Mice; Proto-Oncogene Proteins c-myc; Small Cell Lung Carcinoma; Telomere-Binding Proteins
PubMed: 34344693
DOI: 10.1158/2159-8290.CD-21-0441 -
Cancer Discovery Jul 2020Infant high-grade gliomas appear clinically distinct from their counterparts in older children, indicating that histopathologic grading may not accurately reflect the...
Infant high-grade gliomas appear clinically distinct from their counterparts in older children, indicating that histopathologic grading may not accurately reflect the biology of these tumors. We have collected 241 cases under 4 years of age, and carried out histologic review, methylation profiling, and custom panel, genome, or exome sequencing. After excluding tumors representing other established entities or subgroups, we identified 130 cases to be part of an "intrinsic" spectrum of disease specific to the infant population. These included those with targetable MAPK alterations, and a large proportion of remaining cases harboring gene fusions targeting ( = 31), ( = 21), ( = 9), and ( = 4) as their driving alterations, with evidence of efficacy of targeted agents in the clinic. These data strongly support the concept that infant gliomas require a change in diagnostic practice and management. SIGNIFICANCE: Infant high-grade gliomas in the cerebral hemispheres comprise novel subgroups, with a prevalence of , or gene fusions. Kinase fusion-positive tumors have better outcome and respond to targeted therapy clinically. Other subgroups have poor outcome, with fusion-negative cases possibly representing an epigenetically driven pluripotent stem cell phenotype...
Topics: Gene Fusion; Glioma; Humans; Infant; Neoplasm Grading; Prognosis; Treatment Outcome
PubMed: 32238360
DOI: 10.1158/2159-8290.CD-19-1030 -
Cancer Genomics & Proteomics 2021A fusion gene is the physical juxtaposition of two different genes resulting in a structure consisting of the head of one gene and the tail of the other. Gene fusion is... (Review)
Review
A fusion gene is the physical juxtaposition of two different genes resulting in a structure consisting of the head of one gene and the tail of the other. Gene fusion is often a primary neoplasia-inducing event in leukemias, lymphomas, solid malignancies as well as benign tumors. Knowledge about fusion genes is crucial not only for our understanding of tumorigenesis, but also for the diagnosis, prognostication, and treatment of cancer. Balanced chromosomal rearrangements, in particular translocations and inversions, are the most frequent genetic events leading to the generation of fusion genes. In the present review, we summarize the existing knowledge on chromosome deletions as a mechanism for fusion gene formation. Such deletions are mostly submicroscopic and, hence, not detected by cytogenetic analyses but by array comparative genome hybridization (aCGH) and/or high throughput sequencing (HTS). They are found across the genome in a variety of neoplasias. As tumors are increasingly analyzed using aCGH and HTS, it is likely that more interstitial deletions giving rise to fusion genes will be found, significantly impacting our understanding and treatment of cancer.
Topics: Cytogenetic Analysis; Gene Fusion; Humans; INDEL Mutation
PubMed: 33893073
DOI: 10.21873/cgp.20251 -
Nature Communications Feb 2022Gene fusions can play important roles in tumor initiation and progression. While fusion detection so far has been from bulk samples, full-length single-cell RNA...
Gene fusions can play important roles in tumor initiation and progression. While fusion detection so far has been from bulk samples, full-length single-cell RNA sequencing (scRNA-seq) offers the possibility of detecting gene fusions at the single-cell level. However, scRNA-seq data have a high noise level and contain various technical artifacts that can lead to spurious fusion discoveries. Here, we present a computational tool, scFusion, for gene fusion detection based on scRNA-seq. We evaluate the performance of scFusion using simulated and five real scRNA-seq datasets and find that scFusion can efficiently and sensitively detect fusions with a low false discovery rate. In a T cell dataset, scFusion detects the invariant TCR gene recombinations in mucosal-associated invariant T cells that many methods developed for bulk data fail to detect; in a multiple myeloma dataset, scFusion detects the known recurrent fusion IgH-WHSC1, which is associated with overexpression of the WHSC1 oncogene. Our results demonstrate that scFusion can be used to investigate cellular heterogeneity of gene fusions and their transcriptional impact at the single-cell level.
Topics: Gene Fusion; Sequence Analysis, RNA; Single-Cell Analysis; Software
PubMed: 35228538
DOI: 10.1038/s41467-022-28661-6