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Fusion gene

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In genetics, a fusion gene is a hybrid gene formed from two previously independent genes. It can occur as a result of translocation, interstitial deletion, or chromosomal inversion. Fusion genes have been found to be prevalent in all main types of human neoplasia.[1] The identification of these fusion genes play a prominent role in being a diagnostic and prognostic marker.[2]

A schematic showing the ways a fusion gene can occur at a chromosomal level

History

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The first fusion gene[1] was described in cancer cells in the early 1980s. The finding was based on the discovery in 1960 by Peter Nowell and David Hungerford in Philadelphia of a small abnormal marker chromosome in patients with chronic myeloid leukemia—the first consistent chromosome abnormality detected in a human malignancy, later designated the Philadelphia chromosome.[3] In 1973, Janet Rowley in Chicago showed that the Philadelphia chromosome had originated through a translocation between chromosomes 9 and 22, and not through a simple deletion of chromosome 22 as was previously thought. Several investigators in the early 1980s showed that the Philadelphia chromosome translocation led to the formation of a new BCR::ABL1 fusion gene, composed of the 3' part of the ABL1 gene in the breakpoint on chromosome 9 and the 5' part of a gene called BCR in the breakpoint in chromosome 22. In 1985 it was clearly established that the fusion gene on chromosome 22 produced an abnormal chimeric BCR::ABL1 protein with the capacity to induce chronic myeloid leukemia.

Oncogenes

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It has been known for 30 years that the corresponding gene fusion plays an important role in tumorigenesis.[4] Fusion genes can contribute to tumor formation because fusion genes can produce much more active abnormal protein than non-fusion genes. Often, fusion genes are oncogenes that cause cancer; these include BCR-ABL,[5] TEL-AML1 (ALL with t(12 ; 21)), AML1-ETO (M2 AML with t(8 ; 21)), and TMPRSS2-ERG with an interstitial deletion on chromosome 21, often occurring in prostate cancer.[6] In the case of TMPRSS2-ERG, by disrupting androgen receptor (AR) signaling and inhibiting AR expression by oncogenic ETS transcription factor, the fusion product regulates the prostate cancer.[7] Most fusion genes are found from hematological cancers, sarcomas, and prostate cancer.[1][8] BCAM-AKT2 is a fusion gene that is specific and unique to high-grade serous ovarian cancer.[9]

Oncogenic fusion genes may lead to a gene product with a new or different function from the two fusion partners. Alternatively, a proto-oncogene is fused to a strong promoter, and thereby the oncogenic function is set to function by an upregulation caused by the strong promoter of the upstream fusion partner. The latter is common in lymphomas, where oncogenes are juxtaposed to the promoters of the immunoglobulin genes.[10] Oncogenic fusion transcripts may also be caused by trans-splicing or read-through events.[11]

Since chromosomal translocations play such a significant role in neoplasia, a specialized database of chromosomal aberrations and gene fusions in cancer has been created. This database is called Mitelman Database of Chromosome Aberrations and Gene Fusions in Cancer.[12]

Diagnostics

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Presence of certain chromosomal aberrations and their resulting fusion genes is commonly used within cancer diagnostics in order to set a precise diagnosis. Chromosome banding analysis, fluorescence in situ hybridization (FISH), and reverse transcription polymerase chain reaction (RT-PCR) are common methods employed at diagnostic laboratories. These methods all have their distinct shortcomings due to the very complex nature of cancer genomes. Recent developments such as high-throughput sequencing[13] and custom DNA microarrays bear promise of introduction of more efficient methods.[14]

Evolution

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Gene fusion plays a key role in the evolution of gene architecture. We can observe its effect if gene fusion occurs in coding sequences.[15] Duplication, sequence divergence, and recombination are the major contributors at work in gene evolution.[16] These events can probably produce new genes from already existing parts. When gene fusion happens in non-coding sequence region, it can lead to the misregulation of the expression of a gene now under the control of the cis-regulatory sequence of another gene. If it happens in coding sequences, gene fusion cause the assembly of a new gene, then it allows the appearance of new functions by adding peptide modules into a multi-domain protein.[15] The detecting methods to inventory gene fusion events on a large biological scale can provide insights about the multi modular architecture of proteins.[17][18][19]

Purine biosynthesis

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The purines adenine and guanine are two of the four information encoding bases of the universal genetic code. Biosynthesis of these purines occurs by similar, but not identical, pathways in different species of the three domains of life, the Archaea, Bacteria and Eukaryotes. A major distinctive feature of the purine biosynthetic pathways in Bacteria is the prevalence of gene fusions where two or more purine biosynthetic enzymes are encoded by a single gene.[20] Such gene fusions are almost exclusively between genes that encode enzymes that perform sequential steps in the biosynthetic pathway. Eukaryotic species generally exhibit the most common gene fusions seen in the Bacteria, but in addition have new fusions that potentially increase metabolic flux.

Detection

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In recent years, next generation sequencing technology has already become available to screen known and novel gene fusion events on a genome wide scale. However, the precondition for large scale detection is a paired-end sequencing of the cell's transcriptome. The direction of fusion gene detection is mainly towards data analysis and visualization. Some researchers already developed a new tool called Transcriptome Viewer (TViewer) to directly visualize detected gene fusions on the transcript level.[21]

Research applications

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Biologists may also deliberately create fusion genes for research purposes. The fusion of reporter genes to the regulatory elements of genes of interest allows researches to study gene expression. Reporter gene fusions can be used to measure activity levels of gene regulators, identify the regulatory sites of genes (including the signals required), identify various genes that are regulated in response to the same stimulus, and artificially control the expression of desired genes in particular cells.[22] For example, by creating a fusion gene of a protein of interest and green fluorescent protein, the protein of interest may be observed in cells or tissue using fluorescence microscopy.[23] The protein synthesized when a fusion gene is expressed is called a fusion protein.

See also

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References

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  1. ^ a b c Mitelman F, Johansson B, Mertens F (April 2007). "The impact of translocations and gene fusions on cancer causation". Nature Reviews Cancer. 7 (4): 233–45. doi:10.1038/nrc2091. PMID 17361217. S2CID 26093482.
  2. ^ Prensner JR, Chinnaiyan AM (February 2009). "Oncogenic gene fusions in epithelial carcinomas". Current Opinion in Genetics & Development. 19 (1): 82–91. doi:10.1016/j.gde.2008.11.008. PMC 2676581. PMID 19233641.
  3. ^ "National Academy of Sciences" (PDF). Science. 132 (3438): 1488–501. November 1960. Bibcode:1960Sci...132.1488.. doi:10.1126/science.132.3438.1488. PMID 17739576.
  4. ^ Edwards PA (January 2010). "Fusion genes and chromosome translocations in the common epithelial cancers". The Journal of Pathology. 220 (2): 244–54. doi:10.1002/path.2632. PMID 19921709. S2CID 46435450.
  5. ^ "National Academy of Sciences" (PDF). Science. 132 (3438): 1488–501. November 1960. Bibcode:1960Sci...132.1488.. doi:10.1126/science.132.3438.1488. PMID 17739576.
  6. ^ Tomlins SA, Rhodes DR, Perner S, Dhanasekaran SM, Mehra R, Sun XW, et al. (October 2005). "Recurrent fusion of TMPRSS2 and ETS transcription factor genes in prostate cancer". Science. 310 (5748): 644–8. Bibcode:2005Sci...310..644T. doi:10.1126/science.1117679. PMID 16254181. S2CID 85788789.
  7. ^ Yu J, Yu J, Mani RS, Cao Q, Brenner CJ, Cao X, et al. (May 2010). "An integrated network of androgen receptor, polycomb, and TMPRSS2-ERG gene fusions in prostate cancer progression". Cancer Cell. 17 (5): 443–54. doi:10.1016/j.ccr.2010.03.018. PMC 2874722. PMID 20478527.
  8. ^ Teixeira MR (December 2006). "Recurrent fusion oncogenes in carcinomas". Critical Reviews in Oncogenesis. 12 (3–4): 257–71. doi:10.1615/critrevoncog.v12.i3-4.40. PMID 17425505. S2CID 40770452.
  9. ^ Deciphering the Cancer Transcriptome. 2016
  10. ^ Vega F, Medeiros LJ (September 2003). "Chromosomal translocations involved in non-Hodgkin lymphomas". Archives of Pathology & Laboratory Medicine. 127 (9): 1148–60. doi:10.5858/2003-127-1148-CTIINL. PMID 12946230.
  11. ^ Nacu S, Yuan W, Kan Z, Bhatt D, Rivers CS, Stinson J, et al. (January 2011). "Deep RNA sequencing analysis of readthrough gene fusions in human prostate adenocarcinoma and reference samples". BMC Medical Genomics. 4 (1): 11. doi:10.1186/1755-8794-4-11. PMC 3041646. PMID 21261984.
  12. ^ Mitelman F; Johansson B; Mertens F. "Mitelman Database of Chromosome Aberrations and Gene Fusions in Cancer". Archived from the original on 2016-05-25. Retrieved 2014-09-13.
  13. ^ Maher CA, Kumar-Sinha C, Cao X, Kalyana-Sundaram S, Han B, Jing X, et al. (March 2009). "Transcriptome sequencing to detect gene fusions in cancer". Nature. 458 (7234): 97–101. Bibcode:2009Natur.458...97M. doi:10.1038/nature07638. PMC 2725402. PMID 19136943.
  14. ^ Skotheim RI, Thomassen GO, Eken M, Lind GE, Micci F, Ribeiro FR, et al. (January 2009). "A universal assay for detection of oncogenic fusion transcripts by oligo microarray analysis". Molecular Cancer. 8: 5. doi:10.1186/1476-4598-8-5. PMC 2633275. PMID 19152679.
  15. ^ a b Durrens P, Nikolski M, Sherman D (October 2008). "Fusion and fission of genes define a metric between fungal genomes". PLOS Computational Biology. 4 (10): e1000200. Bibcode:2008PLSCB...4E0200D. doi:10.1371/journal.pcbi.1000200. PMC 2557144. PMID 18949021.
  16. ^ Eichler EE (November 2001). "Recent duplication, domain accretion and the dynamic mutation of the human genome". Trends in Genetics. 17 (11): 661–9. doi:10.1016/s0168-9525(01)02492-1. PMID 11672867.
  17. ^ Enright AJ, Ouzounis CA (2001). "Functional associations of proteins in entire genomes by means of exhaustive detection of gene fusions". Genome Biology. 2 (9): RESEARCH0034. doi:10.1186/gb-2001-2-9-research0034. PMC 65099. PMID 11820254.
  18. ^ Yanai I, Derti A, DeLisi C (July 2001). "Genes linked by fusion events are generally of the same functional category: a systematic analysis of 30 microbial genomes". Proceedings of the National Academy of Sciences of the United States of America. 98 (14): 7940–5. Bibcode:2001PNAS...98.7940Y. doi:10.1073/pnas.141236298. PMC 35447. PMID 11438739.
  19. ^ Pasek S, Risler JL, Brézellec P (June 2006). "Gene fusion/fission is a major contributor to evolution of multi-domain bacterial proteins". Bioinformatics. 22 (12): 1418–23. doi:10.1093/bioinformatics/btl135. PMID 16601004.
  20. ^ Chua SM, Fraser JA (November 2020). "Surveying purine biosynthesis across the domains of life unveils promising drug targets in pathogens". Immunology & Cell Biology. 98 (10): 819–831. doi:10.1111/imcb.12389. PMID 32748425.
  21. ^ Supper J, Gugenmus C, Wollnik J, Drueke T, Scherf M, Hahn A, et al. (January 2013). "Detecting and visualizing gene fusions". Methods. 59 (1): S24-8. doi:10.1016/j.ymeth.2012.09.013. PMID 23036331.
  22. ^ Hartwell, Leland H.; et al. (2011). Genetics : from genes to genomes (4th ed.). New York: McGraw-Hill. pp. 533–534. ISBN 978-0073525266.
  23. ^ Prendergast FG, Mann KG (August 1978). "Chemical and physical properties of aequorin and the green fluorescent protein isolated from Aequorea forskålea". Biochemistry. 17 (17): 3448–53. doi:10.1021/bi00610a004. PMID 28749.
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  • ChiTaRS 5.0: The Improved Database of Chimeric Ttanscripts and RNA-seq Data.
  • ChiPPI Archived 2021-11-10 at the Wayback Machine: The Server Protein-Protein Interaction of Chimeric Proteins.
  • ChimerDB 2.0: a knowledgebase for fusion genes updated.
  • dbCRID: a new, comprehensive database of human CR events and associated diseases (both tumor and non-tumor) with detailed documentation of the CR events.
  • Mitelman Database Archived 2016-05-25 at the Wayback Machine: a database relates chromosomal aberrations to tumor characteristics, based either on individual cases or associations.
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