Proteomic Identification of Oncogenic Chromosomal Translocation Partners Encoding Chimeric Anaplastic Lymphoma Kinase Fusion Proteins (original) (raw)
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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 ...
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.
Antigenicity of fusion proteins from sarcoma-associated chromosomal translocations
Cancer research, 2001
Synovial sarcoma (SS), clear cell sarcoma (CCS), and desmoplastic small round cell tumor (DSRCT) are soft-tissue malignancies occurring primarily in adolescents and young adults. These tumors contain specific chromosomal translocations that fuse the 5' region of one gene with the 3' region of another, resulting in the formation of characteristic fusion proteins. These translocations are unique to tumor cells and may be required for persistence, thereby serving as targets for immunotherapy. It was hypothesized that the fusion breakpoint sequences associated with SS, CCS, and DSRCT can serve as tumor-specific neoantigens. To test this, peptides corresponding to the fusion breakpoints were designed and assessed for ability to bind to various class I HLA molecules. Two peptides derived from the SS breakpoint specifically bind the HLA-B7 antigen, and a 10-amino acid minimal epitope was identified for this interaction. Specific binding of a SS peptide and a CCS peptide to HLA-B27 ...
Chromosomal Translocation Engineering to Recapitulate Primary Events of Human Cancer
Cold Spring Harbor Symposia on Quantitative Biology, 2005
The molecular pathology of cancer and possible new therapies have been a major concern of molecular biology since the first gene cloning experiments opened the possibility to clone, sequence, and study mutations in tumor cells. The very early observations of chromosomal changes in tumor cells (Boveri 1914) reflected genomic instability and raised the possibility of mutant proteins on the cancer cell surface to which antibodies might bind and elicit specific cell killing. There are a few examples of this, and most mutant proteins are firmly ensconced inside the cells and not available for antibody-mediated cell killing. Thus, although many mutations have been discovered, few specific therapies have been developed based on the molecular observations. Nevertheless, the cancer-specific mutations remain tantalizing targets for new cancer therapies. Cancers have somatic mutations ranging from point mutations in genes like those of the RAS family (for review, see Hanahan and Weinberg 2000), which create constitutively active signal transduction molecules (Fig. 1), to genes activated after chromosomal translocations, such as the CMYC gene in Burkitt's lymphoma, and to fusion genes created uniquely in cancer cells by chromosomal translocations, such as the BCR-ABL gene fusion (for review, see Rabbitts 1994). As a range of genes involved in chromosomal translocations was identified, some common features began to emerge, especially in the acute cancers (hematopoietic and mesenchymal tumors) which invariably involve transcription factors whose normal role in cell fate decisions (Cleary 1991; Rabbitts 1991) is subverted (the master gene model; Rabbitts 1991). These transcription factors are often involved in protein-protein interactions. For instance, the T-cell leukemia genes LMO2 and TAL1/SCL are activated by distinct chromo
Fusion oncogenes in tumor development
Seminars in Cancer Biology, 2005
Currently, all identified fusion oncogenes are found in rare tumor forms, and most of them only in specific tumor types. Some fusion oncogenes are frequent in healthy individuals suggesting that they rarely induce tumor growth. Multiple double-strand breaks that cluster in time and space increases the risk for formation of fusion oncogenes genes. The normal cell type specific spatial distribution of chromatin and genes in interphase nuclei may affect the risk for fusion of specific genes. Transcriptional orientation, splicing of reading frames, size and sequences of breakpoint introns are other risk factors. The biological activity of fusion oncoproteins is the most important factor for penetrance. The effects in specific target cells may explain the tumor type specificity of most fusion oncogenes.
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.
Haematologica, 2009
Background The formation of fusion genes plays roles in both oncogenesis and evolution by facilitating the acquisition of novel functions. Here we describe the first example of a human polymorphic in-frame fusion of two unrelated genes associated with a copy number variant. Design and Methods Array comparative genomic hybridization was used to identify cryptic oncogenic fusion genes. Fusion gene structure and origin was examined using molecular biological and computational methods. Phenotype associations were examined using PopGen cohorts. Results Targeted array comparative genomic hybridization to identify cryptic oncogenic fusion genes in patients with atypical myeloproliferative neoplasms identified a 111 kb amplification with breakpoints within the TRK-fused gene (TFG, a target of translocations in lymphoma and thyroid tumors) and G-protein-coupled receptor 128 (GPR128) resulting in an expressed in-frame TFG-GPR128 fusion transcript. The fusion gene was also identified in healthy individuals at a frequency of 0.02 (3/120). Normally both genes are in identical orientations with TFG immediately downstream of GPR128. In individuals with a copy number variant amplification, one or two copies of the TFG-GPR128 fusion are found between the two parental genes. The breakpoints share a region of microhomology, and haplotype and microsatellite analysis indicate a single ancestral origin. Analysis of PopGen cohorts showed no obvious phenotype association. An in silico search of EST databases found no other copy number variant amplification-associated fusion transcripts, suggesting that this is an uncommon event. Conclusions The finding of a polymorphic gene fusion in healthy individuals adds another layer to the complexity of human genome variation and emphasizes the importance of careful discrimination of oncogenic changes found in tumor samples from non-pathogenic normal variation.
Abstract: Chromosomal translocations that results in formation and activation of fusion oncogenes are observed in numerous solid malignancies since years back. Expression of fusion kinases in these cancers drives the initiation & progression that ultimately leads to tumour development and thus comes out to be clinically imperative in terms of diagnosis and treatment of cancer. Nonetheless, molecular mechanisms beneath these ranslocations remained unexplored consequently limiting our knowledge of carcinogenesis and hence is the current field where further research is required. The issue of prime focus is the recision with which the chromosomes breaks and reunites within genome. Characterization of Genomic sequences located at Breakpoint region may direct us towards the thorough understanding of mechanism leading to chromosomal rearrangement. A unique computational multi-parametric analysis was performed for characterization of genomic sequence within and around breakpoint region. Thi...
The role of chromosomal alterations in human cancer development
Journal of Cellular Biochemistry, 2007
Cancer cells become unstable and compromised because several cancer-predisposing mutations affect genes that are responsible for maintaining the genomic instability. Several factors influence the formation of chromosomal rearrangements and consequently of fusion genes and their role in tumorigenesis. Studies over the past decades have revealed that recurring chromosome rearrangements leading to fusion genes have a biological and clinical impact not only on leukemias and lymphomas, but also on certain epithelial tumors. With the implementation of new and powerful cytogenetic and molecular techniques the identification of fusion genes in solid tumors is being facilitated. Overall, the study of chromosomal translocations have revealed several recurring themes, and reached important insights into the process of malignant transformation. However, the mechanisms behind these translocations remain unclear. A more thorough understanding of the mechanisms that cause translocations will be aided by continuing characterization of translocation breakpoints and by developing in vitro and in vivo model systems that can generate chromosome translocation.
Genomic Hallmarks of Genes Involved in Chromosomal Translocations in Hematological Cancer
PLoS Computational Biology, 2012
Reciprocal chromosomal translocations (RCTs) leading to the formation of fusion genes are important drivers of hematological cancers. Although the general requirements for breakage and fusion are fairly well understood, quantitative support for a general mechanism of RCT formation is still lacking. The aim of this paper is to analyze available highthroughput datasets with computational and robust statistical methods, in order to identify genomic hallmarks of translocation partner genes (TPGs). Our results show that fusion genes are generally overexpressed due to increased promoter activity of 59 TPGs and to more stable 39-UTR regions of 39 TPGs. Furthermore, expression profiling of 59 TPGs and of interaction partners of 39 TPGs indicates that these features can help to explain tissue specificity of hematological translocations. Analysis of protein domains retained in fusion proteins shows that the co-occurrence of specific domain combinations is non-random and that distinct functional classes of fusion proteins tend to be associated with different components of the gene fusion network. This indicates that the configuration of fusion proteins plays an important role in determining which 59 and 39 TPGs will combine in specific fusion genes. It is generally accepted that chromosomal proximity in the nucleus can explain the specific pairing of 59 and 39 TPGS and the recurrence of hematological translocations. Using recently available data for chromosomal contact probabilities (Hi-C) we show that TPGs are preferentially located in early replicated regions and occupy distinct clusters in the nucleus. However, our data suggest that, in general, nuclear position of TPGs in hematological cancers explains neither TPG pairing nor clinical frequency. Taken together, our results support a model in which genomic features related to regulation of expression and replication timing determine the set of candidate genes more likely to be translocated in hematological tissues, with functional constraints being responsible for specific gene combinations.