Fusion genes
(updated 2016) | CCDC149 (4p15.2) / MSH2 (2p21) | DNAI1 (9p13.3) / MSH2 (2p21) | EPCAM (2p21) / MSH2 (2p21) |
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MSH2 (2p21) / AC018682.6 () | MSH2 (2p21) / MSH2 (2p21) | MSH2 (2p21) / SLC3A1 (2p21) |
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MSH2 (2p21) / TTC7A (2p21) | PARP12 (7q34) / MSH2 (2p21) | REEP3 (10q21.3) / MSH2 (2p21) |
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| | Diagram of the MSH2 protein in scale. Numbers inside the blue boxes indicate the exon from which is translated each part of the protein. The boxes inside represent the DNA binding domain (red), the hMSH3/hMSH6 interaction domain (yellow) and the MutL homologs interaction domain (green); C: Carboxyl-terminal; N: Amino-terminal. |
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| Description | Aminoacids: 934. Molecular Weight: 104.7 kDa. MSH2 is a protein involved in the mismatch repair process after DNA replication. It contains a DNA binding domain and two interaction domains, one for MSH3 or MSH6 and the other for MutL homologs (MLH1 and PMS2), located in two different regions of the gene. |
| Localisation | Nuclear |
| Function | MSH2 can bind to MSH6 or to MSH3 to form the MutS alpha or the MutS beta complexes respectively. While MutS alpha complex binds to base-base and insertion-deletion mismatches, MutS beta only binds to insertion-deletion mismatches. Upon binding to the mismatch, the MutS complex associates with the MutL complex (composed of MLH1 and PMS2), and recruits the proteins needed for DNA excision and repair. (See also: Repair of DNA double-strand breaks |
| Homology | MSH2 is homologue to the bacterial MutS gene and MSH2 homologues are also present in eukaryotes. |
| Note | |
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| Entity | HNPCC (Hereditary Non Polyposis Colorectal Cancer) |
| Disease | Predisposition to develop cancer, preferentially colorectal, but also in endometrium, , urinary tract, stomach, small bowel, biliary tract and brain. |
| Oncogenesis | MSH2 mutations in HNPCC account for about 25% of the total cases approximately. These mutations are inherited in one allele and later the other allele is lost by LOH. This leads to mismatch repair deficiency in this patients, which is the cause of the accumulation of mutations along the genome, causing microsatellite instability (MSI) and promoting tumorigenesis. It has also been described that low levels of MSI characterize MLH1 and MSH2 HNPCC carriers before tumour diagnosis. |
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| Entity | MSI (MicroSatellite Instability) |
| Note | Tumours in which the molecular feature that leads to cancer is the lost of the mismatch repair (MMR) system. |
| Disease | This phenotype is present in 15% of colorectal, gastric and endometrial cancer, and has a lower incidence in some other tissues. |
| Prognosis | MSI tumours have better prognosis than the MicroSatellite Stable (MSS). |
| Oncogenesis | Few sporadic cases and about 25% of the HNPCC are due to different mutations in MSH2. These mutations are germline in HNPCC. |
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| Entity | Muir-Torre syndrome |
| Disease | Coincidence of at least one sebaceous adenoma, epithelioma or carcinoma and one internal malignancy. |
| Oncogenesis | Muir-Torre syndrome is mainly due to inherited MSH2 mutations. |
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| Low levels of microsatellite instability characterize MLH1 and MSH2 HNPCC carriers before tumor diagnosis. |
| Alazzouzi H, Domingo E, Gonz´lez S, Blanco I, Armengol M, Espín E, Plaja A, Schwartz S, Capella G, Schwartz S Jr |
| Human molecular genetics. 2005 ; 14 (2) : 235-239. |
| PMID 15563510 |
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| Microsatellite instability in inherited and sporadic neoplasms. |
| Eshleman JR, Markowitz SD |
| Current opinion in oncology. 1995 ; 7 (1) : 83-89. |
| PMID 7696368 |
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| The human mutator gene homolog MSH2 and its association with hereditary nonpolyposis colon cancer. |
| Fishel R, Lescoe MK, Rao MR, Copeland NG, Jenkins NA, Garber J, Kane M, Kolodner R |
| Cell. 1993 ; 75 (5) : 1027-1038. |
| PMID 8252616 |
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| DNA mismatch repair defects: role in colorectal carcinogenesis. |
| Jacob S, Praz F |
| Biochimie. 2002 ; 84 (1) : 27-47. |
| PMID 11900875 |
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| A founder mutation of the MSH2 gene and hereditary nonpolyposis colorectal cancer in the United States. |
| Lynch HT, Coronel SM, Okimoto R, Hampel H, Sweet K, Lynch JF, Barrows A, Wijnen J, van der Klift H, Franken P, Wagner A, Fodde R, de la Chapelle A |
| JAMA : the journal of the American Medical Association. 2004 ; 291 (6) : 718-724. |
| PMID 14871915 |
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| A genotype-phenotype correlation in HNPCC: strong predominance of msh2 mutations in 41 patients with Muir-Torre syndrome. |
| Mangold E, Pagenstecher C, Leister M, Mathiak M, Rütten A, Friedl W, Propping P, Ruzicka T, Kruse R |
| Journal of medical genetics. 2004 ; 41 (7) : 567-572. |
| PMID 15235030 |
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| DNA mismatch repair and mutation avoidance pathways. |
| Marti TM, Kunz C, Fleck O |
| Journal of cellular physiology. 2002 ; 191 (1) : 28-41. |
| PMID 11920679 |
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| Mismatch repair genes hMLH1 and hMSH2 and colorectal cancer: a HuGE review. |
| Mitchell RJ, Farrington SM, Dunlop MG, Campbell H |
| American journal of epidemiology. 2002 ; 156 (10) : 885-902. |
| PMID 12419761 |
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