Fusion gene

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A fusion gene is a hybrid gene formed from two previously separate genes. It can occur as a result of: translocation, interstitial deletion, or chromosomal inversion.

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

History[edit]

The first fusion gene [1] was discovered in cancer cells in 1960 in the collaboration between Peter Nowell who worked in Pennsylvania School of Medicine and David Hungerford who was a graduate student at the institute for Cancer Research and doing a thesis on human chromosomes at that time. [2]When they cultured human leukemic cells using Edwin Osgood’s method, [3] which came from patients with chronic granulocytic leukemia (CGL), also known as chronic myelogenous leukemia (CML), they noticed chromosomal abnormalities. The abnormalities observed included an extension in length of chromosome 9 and a shortening of chromosome 22 in comparison to normal versions. These abnormalities are caused by two fused genes, each on different chromosomes. Later, scientists learned that the shortening of chromosome 22 produced an abnormal protein, which resulted in the development of CGL. A chromosomal abnormality involving a reciprocal translocation between chromosomes 9 and 22 is called a Philadelphia translocation, and has been found in the genome of a majority of CML cases.[4]

However, it is still not very clear if a single chromosomal translocation event can be enough to induce the tumor progression.[5] Sometimes it just happens in certain leukemia like the event of Philadelphia chromosome.

At present, scientists have identified 358 gene fusions involving 337 different genes. These genes are all described in the main subtypes of human neoplasia.[6] The identification of these fusion genes play a prominent role in being a diagnostic and prognostic marker. [7]

Oncogenes[edit]

It has been known for 30 years that the corresponding gene fusion plays an important role in tumorgenesis.[8] 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,[9] 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.[10] Most fusion genes are found from hematological cancers, sarcomas, and prostate cancer.[11][12]

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.[13] Oncogenic fusion transcripts may also be caused by trans-splicing or read-through events.[14]

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 can be accessed at the following page: http://cgap.nci.nih.gov/Chromosomes/Mitelman.[15]

Diagnostics[edit]

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[16] and custom DNA microarrays bear promise of introduction of more efficient methods.[17]

Research applications[edit]

Biologists may also deliberately create fusion genes for research purposes. 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.[18] The protein synthesized when a fusion gene is expressed is called a fusion protein.

See also[edit]

References[edit]

  1. ^ Mitelman, F; Johansson, B; Mertens, F (2007). "The impact of translocations and gene fusions on cancer causation". Nature reviews. Cancer 7 (4): 233–45. doi:10.1038/nrc2091. PMID 17361217. 
  2. ^ Nowell, PC; Hungerford, DA (1960). "A minute chromosome in chronic granulocytic leukemia" (PDF). Science 132 (3438): 1488–1501 [1497]. doi:10.1126/science.132.3438.1488. 
  3. ^ Osgood, E.E.; Krippaehhe, M.L. (1955). "The gradient tissue culture method". Experimental Cell Research 9 (1): 116–127. 
  4. ^ Nowell, PC; Hungerford, DA (1960). "A minute chromosome in chronic granulocytic leukemia" (PDF). Science 132 (3438): 1488–1501 [1497]. doi:10.1126/science.132.3438.1488. 
  5. ^ Tosato, Valentina; Gruning, Nana-Maria (2013). "Warburg effect and translocation-induced genomic instability: two yeast models for cancer cells". Frontiers in ONCOLOGY 2 (212). doi:10.3389/fonc.2012.00212. 
  6. ^ Mitelman, F; Johansson, B; Mertens, F (2007). "The impact of translocations and gene fusions on cancer causation". Nature reviews. Cancer 7 (4): 233–45. doi:10.1038/nrc2091. PMID 17361217. 
  7. ^ Prensner, John; Chinnaiya, Arul (2009). "Oncogenic gene fusions in epithelial carcinomas". Curr. Opin. Genet. Dev 19 (1): 82–91. doi:10.1016/j.gde.2008.11.008. 
  8. ^ Edwards, Paul (2009). "Fusion genes and chromosome translocations in the common epithelial cancers". Journal of Pathology 220: 244–254. doi:10.1002/path.2632. 
  9. ^ Nowell, PC; Hungerford, DA (1960). "A minute chromosome in chronic granulocytic leukemia" (PDF). Science 132 (3438): 1488–1501 [1497]. doi:10.1126/science.132.3438.1488. 
  10. ^ Tomlins, SA; Rhodes, DR; Perner, S; Dhanasekaran, SM; Mehra, R; Sun, XW; Varambally, S; Cao, X et al. (2005). "Recurrent fusion of TMPRSS2 and ETS transcription factor genes in prostate cancer". Science 310 (5748): 644–8. doi:10.1126/science.1117679. PMID 16254181. 
  11. ^ Mitelman, F; Johansson, B; Mertens, F (2007). "The impact of translocations and gene fusions on cancer causation". Nature reviews. Cancer 7 (4): 233–45. doi:10.1038/nrc2091. PMID 17361217. 
  12. ^ Teixeira, MR (2006). "Recurrent fusion oncogenes in carcinomas". Critical reviews in oncogenesis 12 (3–4): 257–71. PMID 17425505. 
  13. ^ Vega, F; Medeiros, LJ (2003). "Chromosomal translocations involved in non-Hodgkin lymphomas". Archives of pathology & laboratory medicine 127 (9): 1148–60. doi:10.1043/1543-2165(2003)127<1148:CTIINL>2.0.CO;2 (inactive 2014-03-23). PMID 12946230. 
  14. ^ Nacu, S; Yuan, W; Kan, Z; Bhatt, D; Rivers, CS; Stinson, J; Peters, BA; Modrusan, Z; Jung, K; Seshagiri, Somasekar; Wu, Thomas D (2011). "Deep RNA sequencing analysis of readthrough gene fusions in human prostate adenocarcinoma and reference samples". BMC Med Genomics 4 (1): 11. doi:10.1186/1755-8794-4-11. PMC 3041646. PMID 21261984. 
  15. ^ Tosato, Valentina; Gruning, Nana-Maria (2013). "Warburg effect and translocation-induced genomic instability: two yeast models for cancer cells". Frontiers in ONCOLOGY 2 (212). doi:10.3389/fonc.2012.00212. 
  16. ^ Maher, CA; Kumar-Sinha, C; Cao, X; Kalyana-Sundaram, S; Han, B; Jing, X; Sam, L; Barrette, T et al. (2009). "Transcriptome Sequencing to Detect Gene Fusions in Cancer". Nature 458 (7234): 97–101. doi:10.1038/nature07638. PMC 2725402. PMID 19136943. 
  17. ^ Skotheim, RI; Thomassen, GO; Eken, M; Lind, GE; Micci, F; Ribeiro, FR; Cerveira, N; Teixeira, MR; Heim, S; Rognes, Torbjørn; Lothe, Ragnhild A (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. 
  18. ^ Prendergast, FG; Mann, KG (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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