1. The Role of MSH2 in Hereditary Non-Polyposis Colon Cancer
Joe McClellan
Biol 445 Cancer Biology
Spring 09

2. 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)

3. DNA Mismatch Repair
Discovery of MSH2
Molecular role of MSH2
MSH2 in Colon Cancer

4. 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.

5. The discovery of MSH2 in humans
Mutant yeast lacking MMR
HNPCC Patients
Microsatellite Instability
Cloning of human MSH2

6. MSH2 works with MSH3/MSH6 to locate replication errors
MLH1 dimer binds MSH2 complex and recruits other MMR proteins
Helleman et al. BMC Cancer :201

7. MSH2 is a tumor suppressor gene
Inherit one bad copy
-Still functional MMR
Loss of Heterozygosity
-No MMR system
MSH2
MSH2
MSH2
MSH2

8. Why Colon Cancer? Normal Colon epithelial cells responsive to TGF-β
TGF-β regulates cell proliferation and differentiation (

9. TGF-β RII is mutated as a result of MMR inactivation
Figure The Biology of Cancer (© Garland Science 2007)

10. 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!

11. Mouse TGF-β RII does not have poly-A microsatellite
Gene more stable during replication, less likely to slip
(Jacob and Praz, 2002)

12. 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

13. 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) :
W. Kohlmann, S. B. Gruber. “Hereditary Non-Polyposis Colon Cancer.” Gene Reviews. (29 Nov. 2006). 1 March
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): (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.