fusion transcript discovery

Genetic rearrangements that fuse an androgen-regulated promoter area with a protein-coding portion of an originally androgen-unaffected gene are frequent in prostate cancer, with the fusion between transmembrane serine protease 2 (TMPRSS2) and ETS transcription factor ERG (ERG) (TMPRSS2-ERG fusion) being the most prevalent. Conventional hybridization- or amplification-based methods can test for the presence of expected gene fusions, but the exploratory analysis of currently unknown fusion partners is often cost-prohibitive...

Rare NTRK-driven malignant neoplasms can be effectively inhibited by anti-TRK agents. The discovery of NTRK1/2/3-rich tumours in papillary thyroid cancer (PTC) patients is a precondition for the rapid identification of NTRK fusion tumours. Knowledge of NTRK gene activation is critical to accurately detect NTRK status. A total of 229 BRAF V600E-negative samples from PTC patients were analysed in this study. Break-apart fluorescence in situ hybridisation (FISH) was performed to detect RET fusion. NTRK status was analysed using FISH, DNA- and RNA-based next-generation sequencing (NGS), and quantitative reverse transcription-polymerase chain reaction (RT-qPCR)...

BACKGROUND: Arsenic (As) with various chemical forms, including inorganic arsenic and organic arsenic, is the most prevalent water and environmental toxin. This metalloid occurs worldwide and many of its forms, especially arsenite [As(III)], cause various diseases including cancer. Organification of arsenite is an effective way for organisms to cope with arsenic toxicity. Microbial communities are vital contributors to the global arsenic biocycle and represent a promising way to reduce arsenite toxicity...

Adenocarcinoma of the esophagus (EAC) and gastroesophageal junction (GEJ-AC) is associated with poor prognosis, treatment resistance and limited systemic therapeutic options. To deeply understand the genomic landscape of this cancer type, and potentially identify a therapeutic target in a neoadjuvant chemotherapy non-responder 48-year-old man, we adopted a multi-omic approach. We simultaneously evaluated gene rearrangements, mutations, copy number status, microsatellite instability and tumor mutation burden...

The discovery of neurotrophic tyrosine receptor kinase (NTRK) gene fusions as pan-tumor oncogenic drivers has led to new personalized therapies in oncology. Recent studies investigating NTRK fusions among mesenchymal neoplasms have identified several emerging soft tissue tumor entities displaying various phenotypes and clinical behaviors. Among them, tumors resembling lipofibromatosis or malignant peripheral nerve sheath tumors often harbor intra-chromosomal NTRK1 rearrangements, while most infantile fibrosarcomas are characterized by canonical ETV6::NTRK3 fusions...

UNLABELLED: Gene fusions and their chimeric products are typically considered hallmarks of cancer. However, recent studies have found chimeric transcripts in non-cancer tissues and cell lines. In addition, efforts to annotate structural variation at large scale have found examples of gene fusions with potential to produce chimeric transcripts in normal tissues. In this report, we provide a means for targeting population-specific chimeric RNAs to enrich for those generated by gene fusion events...

The discovery of regulatory domains has been limited to the investigation of transcription factors and homologous protein sequences. In this issue of Cell Genomics , motivated by an oncogenic protein fusion, Tak et al.1 direct the regulatory potential of a nontraditional effector domain to novel genomic loci with fusions to programmable DNA-binding domains.

Human acetyltransferases MOZ and MORF are implicated in chromosomal translocations associated with aggressive leukemias. Oncogenic translocations involve the far amino terminus of MOZ/MORF, the function of which remains unclear. Here, we identified and characterized two structured winged helix (WH) domains, WH1 and WH2, in MORF and MOZ. WHs bind DNA in a cooperative manner, with WH1 specifically recognizing unmethylated CpG sequences. Structural and genomic analyses show that the DNA binding function of WHs targets MORF/MOZ to gene promoters, stimulating transcription and H3K23 acetylation, and WH1 recruits oncogenic fusions to HOXA genes that trigger leukemogenesis...

UNLABELLED: Small-cell lung cancer (SCLC) is an aggressive neuroendocrine lung cancer. Oncogenic MYC amplifications drive SCLC heterogeneity, but the genetic mechanisms of MYC amplification and phenotypic plasticity, characterized by neuroendocrine and nonneuroendocrine cell states, are not known. Here, we integrate whole-genome sequencing, long-range optical mapping, single-cell DNA sequencing, and fluorescence in situ hybridization to find extrachromosomal DNA (ecDNA) as a primary source of SCLC oncogene amplifications and driver fusions...

Fusion of the ETS (E-26 transformation-specific)-related gene (ERG) with transmembrane serine protease 2 (TMPRSS2) is a crucial step in the occurrence and progression of approximately 50% of prostate cancers. Despite significant progress in drug discovery, ERG inhibitors have yet to be approved for the clinical treatment of prostate cancer. In this study, we used computer-aided drug design (CADD)-based virtual screening to screen for potential inhibitors of ERG. In vivo and in vitro methods revealed that nifuroxazide inhibited the proliferation of a TMPRSS2:ERG fusion-positive prostate cancer cell line (VCaP) with an IC50 lower than that of ERG-negative prostate cancer cell lines (LNCaP, DU145 and WPMY cells)...

Chromosomal translocations in cancer genomes, key players in many types of cancers, generate chimeric proteins that drive oncogenesis. Genomes with chromosomal rearrangements can also produce fusion circular RNAs (f-circRNAs) by backsplicing of chimeric transcripts, as first shown in leukemias with PML::RARα and KMT2A::MLLT3 translocations and later in solid cancers. F-circRNAs contribute to the oncogenic processes and reinforce the oncogenic activity of chimeric proteins. In leukemia with KMT2A::AFF1 (MLL::AF4) fusions, we previously reported specific alterations of circRNA expression, but nothing was known about f-circRNAs...

Ewing sarcoma is a cancer of bone and soft tissue in children driven by EWS::ETS fusion, most commonly EWS::FLI1. Because current cytotoxic chemotherapies are not improving the survival of those with metastatic or recurrent Ewing sarcoma cases, there is a need for novel and more effective targeted therapies. While EWS::FLI1 is the major driver of Ewing sarcoma, EWS::FLI1 has been difficult to target. A promising alternative approach is to identify and target the molecular vulnerabilities created by EWS::FLI1...

Extensive investigation of gene fusions in cancer has led to the discovery of novel biomarkers and therapeutic targets. To date, most studies have neglected chromosomal rearrangement-independent fusion transcripts and complex fusion structures such as double or triple-hop fusions, and fusion-circRNAs. In this review, we untangle fusion-related terminology and propose a classification system involving both gene and transcript fusions. We highlight the importance of RNA-level fusions and how long-read sequencing approaches can improve detection and characterization...

Alternative splicing (AS) and alternative polyadenylation (APA) are common mechanisms in eukaryotes to increase the complexity of transcriptomes and subsequently proteomes. Analysis of long reads transcriptomics data can result in the discovery of novel transcripts, splice sites, AS or APA events. Gossypium arboreum is an important cultivated cotton species and a putative contributor of the A sub-genome to the modern tetraploid cotton; and inherently tolerant to several biotic and abiotic stresses. Specifically, its variety 'FDH228' is considered to be an important resistance source...

Background: The clinical significance of majority oncogenic novel fusions is still unknown due to scarcity. Reciprocal ROS1 translocation is a rare form of ROS1 fusion and has not yet been clearly analyzed. Case presentation: A 44-year-old Chinese woman with a large dimension in the left lobe of the lung was admitted to the hospital with IVB lung adenocarcinoma. It was discovered that intron 28 of ROS1 and intron 6 of CD74 produced a unique reciprocal ROS1 rearrangement...

Capicua transcriptional repressor (CIC)-rearranged sarcoma, belonging to the undifferentiated round cells sarcoma family, is characterized by high metastatic rate and poor chemo response. CIC sarcoma represents a new entity harboring the recurrent chromosomal translocation between CIC and, in most of the cases, DUX4 . CIC-DUX4 imposes a CIC-specific transcriptional signature, which drives cell transformation, proliferation, and migration. While the discovery of the fusion represented the first evidence of a role of CIC in cancer, a complete comprehension of CIC-rearranged activity is still required before providing new potential avenues for therapy...

Human respiratory syncytial virus (hRSV) infection is a leading cause of severe respiratory tract infections. Effective, directly acting antivirals against hRSV are not available. We aimed to discover new and chemically diverse candidates to enrich the hRSV drug development pipeline. We used a two-step screen that interrogates compound efficacy after primary infection and a consecutive virus passaging. We resynthesized selected hit molecules and profiled their activities with hRSV lentiviral pseudotype cell entry, replicon, and time-of-addition assays...

Background: Solitary fibrous tumors (SFTs) are relatively rare spindle cell neoplasms uncommonly seen in dermatology practice. Initially discovered as a pleural tumor, SFTs have also been found in extra-pleural sites including the skin and soft tissues. When arising within the dermis or subcutis they are termed superficial SFTs, where they often present as solitary, unilateral, slow growing superficial masses. Histologically, they are composed of spindle cells arranged in a "patternless" pattern with hemangiopericytoma-like vessels dispersed throughout...

Early and accurate detection of viruses in clinical and environmental samples is essential for effective public healthcare, treatment, and therapeutics. While PCR detects potential pathogens with high sensitivity, it is difficult to scale and requires knowledge of the exact sequence of the pathogen. With the advent of next-gen single-cell sequencing, it is now possible to scrutinize viral transcriptomics at the finest possible resolution-cells. This newfound ability to investigate individual cells opens new avenues to understand viral pathophysiology with unprecedented resolution...

Acute myeloid leukaemia (AML) is a rapidly fatal blood cancer that is characterised by the accumulation of immature myeloid cells in the blood and bone marrow as a result of blocked differentiation. Methods which identify master transcriptional regulators of AML subtype-specific leukaemia cell states and their combinations could be critical for discovering novel differentiation-inducing therapies. In this proof-of-concept study, we demonstrate a novel utility of the Mogrify® algorithm in identifying combinations of transcription factors (TFs) and drugs, which recapitulate granulocytic differentiation of the NB4 acute promyelocytic leukaemia (APL) cell line, using two different approaches...