Oncogenic gene fusions in primary colon cancers
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ABSTRACT:
PROVIDER: EGAS00001002197 | EGA |
REPOSITORIES: EGA
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Project description:Fusion genes can be oncogenic drivers in a variety of cancer types and represent potential targets for targeted therapy. The BRAF gene is frequently involved in oncogenic fusions, with fusion frequencies of 0.2-3% throughout different cancers. However, BRAF fusions rarely occur in the same gene configuration, potentially challenging personalized therapy design. In particular, the influence that is imposed by the wide variety of fusion partners on the oncogenic role of BRAF during tumor growth and drug response is unknown. Here, we used patient-derived colorectal cancer organoids to functionally characterize and cross-compare previously identified BRAF fusions containing various partner genes (AGAP3, DLG1 and TRIM24) with respect to cellular behaviour, downstream signaling activation and response to targeted therapies. We demonstrate that 5’ partner choice of BRAF fusions affects their subcellular localization and intracellular signaling capacity. In particular the DLG1-BRAF fusion protein showed distinct localization to the plasma membrane and exhibited increased activation of downstream MAPK signaling under unperturbed conditions. Moreover, phosphoproteomics and RNA sequencing identified distinct subsets of affected signaling pathways and altered gene expression of BRAF fusions. The different BRAF fusions exhibited varying sensitivities to simultaneous targeted inhibition of MEK and the EGF receptor family. However, all BRAF fusions conveyed resistance to targeted monotherapy against the EGF receptor family, suggesting that BRAF fusions should be screened alongside other MAPK pathway alterations to identify mCRC patients to exclude from cetuximab treatment
2020-01-16 | PXD013461 | Pride
Project description:The identification and clinical validation of cancer driver genes are essential to accelerate the translational transition of cancer genomics, as well as to find clinically confident targets for the therapeutic intervention of cancers. Here we identified recurrent LMNA-NTRK1 and TPM3-NTRK1 fusions in Korean patients with colon cancer (3 out of 147, 2%) through next-generation RNA sequencing (RNA-seq). NTRK1 fusions were mutually exclusive oncogenic drivers of colon cancer that were accompanied with in vitro potential of colony formation and in vivo tumorigenicity comparable to KM12, a human colon cancer cell line harboring TPM3-NTRK1 fusion. NTRK1-encoded TrkA protein was prevalent in 11 out of 216 Korean (5.1%) and 28 out of 472 Chinese patients (5.9%) from independent cohorts, respectively. The expression level of TrkA was significantly correlated with NTRK1 fusion (p = 0.0192), which was verified by a fluorescence in situ hybridization (FISH). Korean patients with TrkA-positive colon cancer had a marginal but significant shorter overall survival time than TrkA-negative colon cancer [hazard ratio (HR) = 0.5346, 95% confidential interval (CI) = 0.2548-0.9722, p = 0.0411]. In addition, KM12 cell line was sensitive to selective TrkA inhibitors. These results demonstrate that NTRK1 fusion is granted as a clinically relevant target for therapeutic intervention of colon cancer.
2021-07-31 | GSE180440 | GEO
Project description:Kinase fusions are considered oncogenic drivers in numerous types of cancer. In lung adenocarcinoma 5-10% of patients harbor kinase fusions. The most frequently detected kinase fusion involves the Anaplastic Lymphoma Kinase (ALK) and Echinoderm Microtubule-associated protein-Like 4 (EML4). In addition, oncogenic kinase fusions involving the tyrosine kinases RET and ROS1 are found in smaller subsets of patients. In this study, we employed quantitative mass spectrometry-based phosphoproteomics to define the cellular tyrosine phosphorylation patterns induced by different oncogenic kinase fusions identified in patients with lung adenocarcinoma. We show that the cellular expression of the kinase fusions leads to widespread tyrosine phosphorylation. Direct comparison of different kinase fusions demonstrates that the kinase part and not the fusion partner primarily defines the phosphorylation pattern. The tyrosine phosphorylation patterns differed between ALK, ROS1 and RET fusions, suggesting that oncogenic signaling induced by these kinases involves the modulation of different cellular processes.
2021-04-27 | PXD021904 | Pride
Project description:Identification of Targetable FGFR Gene Fusions in Diverse Cancers
| PRJNA191587 | ENA
Project description:NTRK1 fusions for the therapeutic intervention of Korean patients with colon cancer
| PRJNA748264 | ENA
Project description:Fusions involving tyrosine kinases are oncogenic drivers in lung cancer and other solid tumors but also mediate resistance to targeted therapy. Despite gene rearrangements involving tyrosine kinases tending to show recurrent patterns in solid tumors, little is known about their mechanisms of formation and their selection process. To elucidate these mechanisms, we developed a functional high-throughput, genome-wide translocation sequencing (F-HTGTS) approach. We applied F-HTGTS to lung cancer cells under the selective pressure of EGFR inhibition to map genome-wide translocations when a DNA double-strand break occurs in the ALK, RET, ROS1 or NTRK1 tyrosine kinase. We found that translocations form spontaneously with several partners in the genome, generate functional fusion proteins and induce resistance to EGFR inhibitors. Several of these proteins reproduce precisely the fusions found in NSCLC patients either as original driver events or secondary to development of resistance to targeted therapy. Therefore, F-HTGTS is an approach that allows rapid and comprehensive mapping of tyrosine kinase fusions in the genome from common oncogenic kinases and provide insights on their mechanisms of formation.
2024-04-29 | GSE167155 | GEO
Project description:Background. Most colorectal cancers (CRC) arise in a progression through adenoma to carcinoma phenotypes as a consequence of altered genetic information. Clinical progression of CRC may occur in parallel with distinctive signaling alterations. We designed multidirectional analyses integrating microarray-based data with biostatistics and bioinformatics to elucidate the signaling and metabolic alterations underlying CRC development in the adenoma-carcinoma sequence. Methodology/Principal Findings. Studies were performed on normal mucosa, adenoma, and CRC samples obtained during surgery or colonoscopy. Collections of cryostat sections prepared from the tissue samples were evaluated by a pathologist to control the relative cell type content. RNA was isolated from 105 macro- and 40 microdissected specimens. The measurements were done using Affymetrix GeneChip HG-U133plus2, and probe set data were generated using two normalization algorithms: MAS5 and GCRMA with LVS. The data were evaluated using pair-wise comparisons and data decomposition into SVD modes. The method selected for the functional analysis used the Kolmogorov-Smirnov test. Based on a consensus of the results obtained by two tissue handling procedures, two normalization algorithms, and two probe set sorting criteria, we identified six KEGG signaling and metabolic pathways (cell cycle, DNA replication, p53 signaling pathway, purine metabolism, pyrimidine metabolism, and RNA polymerase) that are significantly altered in both macro- and microdissected tumor samples compared to normal colon. On the other hand, pathways altered between benign and malignant tumors were identified only in the macrodissected tissues. Conclusion/Significance. Multidirectional analyses of microarray data allow the identification of essential signaling alterations underlying CRC development. Although the proposed strategy is computationally complex and labor–intensive, it may reduce the number of false results. Gene expression profiles of 40 tissue samples representing distant full-thickness normal colon, normal colon mucosa dissected from tumor, adenoma, and carcinoma. Gene expression profiles of 105 tissue samples representing colon carcinomas, adenocarcinomas, and normal colon samples.
2010-08-01 | E-GEOD-20916 | biostudies-arrayexpress
Project description:Oncofusions form when chromosomal translocations join two genes to create a protein with oncogenic properties. The oncogenic ETV6-NTRK3 (EN) gene fusion joins the sterile alpha domain of the ETV6 transcription factor with the tyrosine kinase domain of the neurotrophin-3 receptor NTRK3. Four EN variants with alternating break points have since been detected in a wide range of human cancers. To provide insight into EN oncogenesis, we employed a proximity labeling mass spectrometry approach to define the molecular context of the fusions. We identify 237 high-confidence interactors, which link EN fusions to several key signaling pathways, including ERBB, Insulin and JAK/STAT. We then assess the effects of EN variants on these pathways, and show that the pan NTRK inhibitor selitrectinib (LOXO-195) inhibits the oncogenic activity of EN2, the most common variant. This systems-level analysis of defines the molecular framework in which EN oncofusions operate to promote cancer.
2023-01-13 | MSV000091061 | MassIVE
Project description:Gene fusions (GFs) represent a distinct class of structural variants identified consistently in cancer genomes across multiple cancer types. Several GFs exhibit gain of oncogenic function, and thus, have been the focus for development of efficient targeted therapies. Here, we present a comprehensive landscape of GFs in early-onset sporadic rectal cancer (EOSRC), a poorly studied colorectal cancer (CRC) subtype prevalent in developing countries from the transcriptome analysis of 37 EOSRC samples. Gene Ontology analysis revealed enrichment of unique biological process terms associated with 5’- and 3’- fusion partner genes. An extensive network analysis highlighted several promiscuous genes participating in GF formation. Further, an in-depth evaluation revealed significant association of these promiscuous genes with chromosome fragile sites.
2024-06-27 | GSE253106 | GEO
Project description:Etiology of oncogenic fusions in 5,190 childhood cancers and its clinical and therapeutic implication
| PRJEB55308 | ENA