Fusion oncogenes in tumor development (original) (raw)
Related papers
Seminars in Cancer Biology, 1999
Tumor development in different cell types and tissue locations involves many pathways, distinct genes and exogenous factors. Tumor type-specific chromosome rearrangements resulting in fusion genes or promoter swapping are believed to be involved in the early development of many tumor types. They are present in almost all cases of a particular tumor type and cases have been described that carry only tumor type-specific translocations without any signs of other cytogenetic changes. The mechanisms behind chromosome rearrangements in solid tumors are largely unknown. Radiation is an important factor in thyroid carcinomas but no com-$bmon sequence motifs are made out in the break points of solid tumors. The fusion genes found in sarcomas are dominated by the transcription factor type of genes with the TLS/FUS and EWS series of fusion genes as the largest group. More than 50% of papillary thyroid carcinomas carry fusion proteins with tyrosine kinase activity. Rearrangements involving HMGIC, HMGIY, and PLAG1 are common in benign mesenchymal tumors and salivary gland adenomas. Many recurrent tumor translocations show a strict specificity for tumor type. This specificity can most likely be explained by the specific sets of target genes that are deregulated by the fusion gene products. Identification of the downstream target genes is currently the object of intense research and may provide us with information that will help design better diagnostic tools and eventually find a cure for these diseases.
Oncotarget, 2016
While many solid tumors are defined by the presence of a particular oncogene, the role that this oncogene plays in driving transformation through the acquisition of aneuploidy and overcoming growth arrest are often not known. Further, although aneuploidy is present in many solid tumors, it is not clear whether it is the cause or effect of malignant transformation. The childhood sarcoma, Alveolar Rhabdomyosarcoma (ARMS), is primarily defined by the t(2;13)(q35;q14) translocation, creating the PAX3-FOXO1 fusion protein. It is unclear what role PAX3-FOXO1 plays in the initial stages of tumor development through the acquisition and persistence of aneuploidy. In this study we demonstrate that PAX3-FOXO1 serves as a driver mutation to initiate a cascade of mRNA and miRNA changes that ultimately reprogram proliferating myoblasts to induce the formation of ARMS. We present evidence that cells containing PAX3-FOXO1 have changes in the expression of mRNA and miRNA essential for maintaining pr...
Fusion genes in solid tumors: an emerging target for cancer diagnosis and treatment
Chinese Journal of Cancer, 2013
Studies over the past decades have uncovered fusion genes, a class of oncogenes that provide immense diagnostic and therapeutic advantages because of their tumor-specific expression. Originally associated with hemotologic cancers, fusion genes have recently been discovered in a wide array of solid tumors, including sarcomas, carcinomas, and tumors of the central nervous system. Fusion genes are attractive as both therapeutic targets and diagnostic tools due to their inherent expression in tumor tissue alone. Therefore, the discovery and elucidation of fusion genes in various cancer types may provide more effective therapies in the future for cancer patients.
Genes that contribute to cancer fusion genes are large and evolutionarily conserved
Cancer Genetics and Cytogenetics, 2009
Numerous cancer fusion genes have been identified and studied, and in some cases, therapy or diagnostic techniques have been designed that are specific to the fusion protein encoded by the fusion gene. There has been little progress, however, in understanding the general features of cancer fusion genes in a way that could provide the foundation for an algorithm for predicting the occurrence of a fusion gene once the chromosomal translocation points have been identified by karyotype analyses. In this study, we used publicly available data sets to characterize 59 cancer fusion genes. The results indicate that all but 17% of the genes involved in fusion events are either relatively large, compared to neighboring genes, or are highly conserved in evolution. These results support a basis for designing algorithms that could have a high degree of predictive value in identifying fusion genes once conventional microscopic analyses have identified the chromosomal breakpoints.
Making of fusion genes in cancer: An in-silico study of mechanism of chromosomal translocations
Chromosomal translocations involve exchange of genetic material between non- homologous chromosomes leading to the formation of a fusion gene with altered function. The clinical consequences of non-random and recurrent chromosomal translocations have been so well understood in carcinogenesis that they serve as diagnostic and prognostic markers and also help in therapy decisions, mainly in leukemia and lymphoma. However, the molecular mechanisms underlying these recurrent genetic exchanges are yet to be understood. Various approaches employed include the extent of the vicinity of the partner chromosomes in the nucleus, DNA sequences at the breakpoints, etc. The present study addresses the stability of DNA sequences at the breakpoint regions using in-silico approach in terms of physicochemical properties such as; AT%, flexibility, melting temperature, enthalpy, entropy, stacking energy and free energy. Changes in these properties may lead to instability of DNA which could affect gene ...
Gene Fusion events in Human Cancers
PENSEE, 2021
Gene fusion is an important type of chromosomal rearrangement. When it comes to cancers, translocation is dominant over other types of chromosomal rearrangements. Fused genes have ability to produce proteins that leads to uncontrolled cell growth. This paper used 86245 datasets about gene fusion mutations from COSMIC database. ABL1 gene was identified as the most common 3' gene, and, BCR gene was identified as most common 5' gene, among all fusion events. Gene fusion between BCR-ABL1 genes identified as the most frequent gene fusion among the data file and mainly causes hematopoietic and lymphoid tissues cancers. Analyzing the about most common cancer-causing fusion genes, translocation sites, primary sites related to each fusion gene is important while developing diagnostic and prognostic tools in cancer studies
Intrinsic Structural Disorder Confers Cellular Viability on Oncogenic Fusion Proteins
PLOS Computational Biology, 2009
Chromosomal translocations, which often generate chimeric proteins by fusing segments of two distinct genes, represent the single major genetic aberration leading to cancer. We suggest that the unifying theme of these events is a high level of intrinsic structural disorder, enabling fusion proteins to evade cellular surveillance mechanisms that eliminate misfolded proteins. Predictions in 406 translocation-related human proteins show that they are significantly enriched in disorder (43.3% vs. 20.7% in all human proteins), they have fewer Pfam domains, and their translocation breakpoints tend to avoid domain splitting. The vicinity of the breakpoint is significantly more disordered than the rest of these already highly disordered fusion proteins. In the unlikely event of domain splitting in fusion it usually spares much of the domain or splits at locations where the newly exposed hydrophobic surface area approximates that of an intact domain. The mechanisms of action of fusion proteins suggest that in most cases their structural disorder is also essential to the acquired oncogenic function, enabling the long-range structural communication of remote binding and/or catalytic elements. In this respect, there are three major mechanisms that contribute to generating an oncogenic signal: (i) a phosphorylation site and a tyrosine-kinase domain are fused, and structural disorder of the intervening region enables intramolecular phosphorylation (e.g., BCR-ABL); (ii) a dimerisation domain fuses with a tyrosine kinase domain and disorder enables the two subunits within the homodimer to engage in permanent intermolecular phosphorylations (e.g., TFG-ALK); (iii) the fusion of a DNA-binding element to a transactivator domain results in an aberrant transcription factor that causes severe misregulation of transcription (e.g. EWS-ATF). Our findings also suggest novel strategies of intervention against the ensuing neoplastic transformations.
PLoS ONE, 2009
Background: The recurrence and non-random distribution of translocation breakpoints in human tumors are usually attributed to local sequence features present in the vicinity of the breakpoints. However, it has also been suggested that functional constraints might contribute to delimit the position of translocation breakpoints within the genes involved, but a quantitative analysis of such contribution has been lacking. Methodology: We have analyzed two well-known signatures of functional selection, such as reading-frame compatibility and non-random combinations of protein domains, on an extensive dataset of fusion proteins resulting from chromosomal translocations in cancer. Conclusions: Our data provide strong experimental support for the concept that the position of translocation breakpoints in the genome of cancer cells is determined, to a large extent, by the need to combine certain protein domains and to keep an intact reading frame in fusion transcripts. Additionally, the information that we have assembled affords a global view of the oncogenic mechanisms and domain architectures that are used by fusion proteins. This can be used to assess the functional impact of novel chromosomal translocations and to predict the position of breakpoints in the genes involved.