Download MSH2 deficient mice

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
(Abdel-Rahman et al, 2006)
Prognosis better with HNPCC
than with sporadic colon
cancer
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
Microsatellite Instability
Cloning of human MSH2
HNPCC Patients
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&in
fId=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
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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.