The Role of MSH2 in Hereditary Non-Polyposis Colon Cancer Joe McClellan Biol 445 Cancer Biology Spring 09
Hereditary Non-polyposis Colon Cancer 5-8% of all colon cancer Predisposition to colon cancer with very high penetrance HNPCC: 50-80% chance Normal: 5% chance Treatment: Full colectomy, followed by ileorectal anastomosis Still at risk for other cancers: endometrial, small intestine, ureter, renal pelvis Prognosis better with HNPCC than with sporadic colon cancer (Abdel-Rahman et al, 2006)
DNA Mismatch Repair Discovery of MSH2 Molecular role of MSH2 MSH2 in Colon Cancer
The DNA Mismatch Repair (MMR) System locates and repairs DNA replication errors Microsatellites: sequences made up of short, repeated sequences. Ex: AAAAAAAAAAAAA; CACACACACACACACA Microsatellite Instability (MSI): When these sequences are longer or shorter than normal.
The discovery of MSH2 in humans Mutant yeast lacking MMR HNPCC Patients Microsatellite Instability Cloning of human MSH2
MSH2 works with MSH3/MSH6 to locate replication errors MLH1 dimer binds MSH2 complex and recruits other MMR proteins Helleman et al. BMC Cancer 2006 6:201
MSH2 is a tumor suppressor gene Inherit one bad copy -Still functional MMR Loss of Heterozygosity -No MMR system MSH2 MSH2 MSH2 MSH2
Why Colon Cancer? Normal Colon epithelial cells responsive to TGF-β TGF-β regulates cell proliferation and differentiation (http://www.hbt.nl/infopages/index.asp?MODUS=fullarticle&infId=37)
TGF-β RII is mutated as a result of MMR inactivation Figure 12.28 The Biology of Cancer (© Garland Science 2007)
MSH2 knockout mice MSH2 deprived ES cells: Microsatellite Instability MSH2 deficient mice: viable, no major abnormalities, but highly susceptible to lymphoid tumors Human w/o MSH2 Colon cancer Mouse w/o MSH2 Lymphoid cancer!
Mouse TGF-β RII does not have poly-A microsatellite Gene more stable during replication, less likely to slip (Jacob and Praz, 2002)
Inherit a bad copy of MSH2 Loss of Heterozygosity (LOH) Inactivation of MMR Increased Mutation Rate (i.e. Microsatellite Instability) Frameshift Mutation in TGF-β RII Colon epithelial cells unable to respond to TGF- β Proliferation
References R. Fishel, M.K. Lescoe, M.R. Rao, N.G. Copeland, N.A. Jenkins, J. Garber, M. Kane, R. Kolodner, The human mutator gene homolog MSH2 and its association with hereditary nonpolyposis colon cancer, Cell 75 (1993) 1027–1038. S. Jacob and F. Praz. DNA mismatch repair defects: role in colorectal carcinogenesis, Biochimie 84 (2002), pp. 27–47. P. Peltomaki. Deficient DNA mismatch repair: a common etiologic factor for colon cancer. Human Molecular Genetics 10 (2001) : 735 2001 W. Kohlmann, S. B. Gruber. “Hereditary Non-Polyposis Colon Cancer.” Gene Reviews. (29 Nov. 2006). 1 March 2009 http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=gene&part=hnpcc S Y Koyama and D K Podolsky. Differential expression of transforming growth factors alpha and beta in rat intestinal epithelial cells. J. Clin. Invest. 83(5): 1768-1773 (1989). W.M. Abdel-Rahman, J.P. Mecklin and P. Peltomaki, The genetics of HNPCC: application to diagnosis and screening, Critical Reviews in Oncology–Hematology 58 (2006), pp. 208–220 V. Stigliano et al. Survival of hereditary non-polyposis colorectal cancer patients compared with sporadic colorectal cancer patients. J Exp Clin Cancer Res. 2008; 27(1): 39.