HNPCC and MLH1

Qi Peng

Cancer Biology

March 30th, 2006

Hereditary Nonpolyposis Colon Cancer (HNPCC)

• An inherited cancer of digestive tract, especially increases risk of colon cancer.

• Increases women’s risk of getting, endometrial and ovarian cancer

• May also cause colon polyps.

Colorectal Cancer Facts

• One of the most common cancers in the world.

• In US alone, around 110,000 new cases every year.

HNPCC Facts

• Responsible for 2% to 7% of all colorectal cancer.

• Inherited in an autosomal dominant pattern.

• Not all who inherit mutations will develop cancer .

Which Genes Went Wrong?

• MLH1, MLH3, MSH2,MSH3,MSH6, and PMS2

• Repair DNA replication errors.

• Mutations in any of these genes greatly increase DNA replication errors.

• Mismatch Repair Pathway.

• Members of mismatch repair (MMR) genes.

What Is MLH1

• MutL homolog 1, colon cancer, nonpolyposis type 2 (E. coli).

• 3p21.3, between bp 37,009,982 to 37,067,340 on chromosome.

What is MLH1

• About 50% of HNPCC caused by MLH1

• a member of MMR genes

• A tumor Suppressor

• Hundreds of MLH1 mutations predispose people to colon cancer

• prevent the production of MLH1 protein• Alter MLH1 protein, so it does not function properly.

Mismatch Repair Pathway

Mismatch Repair Pathway

• Identify and eliminate base–base mismatches and insertion–deletion loops.

• six different MMR proteins are required: MLH1, MLH3, MSH2, MSH3, MSH6, PMS2.

• A sliding clamp model

Mismatch Repair Pathway

Mismatch Repair Pathway

MMP Sliding Clamp Model

MMR Protein

MLH1 and Mismatch Repair Pathway

• MLH1 protein dimerizes with PMS2 to coordinate the interplay between the mismatch recognition complex and other proteins necessary for MMR.

What Went Wrong?

MLH1 can be disrupted by:

• missense mutations

• truncating mutations

• splice site mutations

• large deletions

• genomic rearrangements.

What Went Wrong

• MLH1 acts in a recessive manner at the cellular level

• Therefore, the 2-hit model stands.

• Missense mutations do not eliminate the protein

• Affect DNA binding

• Affect protein- protein interactions.

If MLH1 Gene Does Not Work

• DNA replication errors greatly increases and accumulates as cells continue to divide, which leads to

• MMR Deficiency• Greater genomic

instability• Eventually cancer.

MLH1 and Knock-out mice

• show a replication error phenotype

• Cells are deficient in MMR activity

• Mutant males have no mature sperms

• Mutant females are infertile

MLH1 and Knock-out mice

Bibliography• Bronner, C. E. et al. (1994) “Mutation in the DNA mismatch repair gene

homologue hMLH1 is associated with hereditary nonpolyposis colon cancer.” Nature, 368, 258–261.

• Buermeyer, A.B., Deschenes, S.M., Baker, S.M. and Liskay, R.M. (1999) Mammalian DNA mismatch repair. Annu. Rev. Genet., 33, 533–564.

• Edelmann, Winfried et al . (1996) “Meiotic Pachytene Arrest in MLH1-Deficient Mice”. Cell, 85, 1125-1134.

• Kolodner, R.D. and Marsischky, G.T. (1999) “Eukaryotic mismatch repair. “Curr. Opin. Genet. Dev., 9, 89–96

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• Peltomäki, P., Vasen, H.F.A. and the International Collaborative Group on HNPCC (1997) “Mutations predisposing to hereditary nonpolyposis colorectal cancer: database and results of a collaborative study.” Gastroenterology, 113, 1146–1158.

• Peltomäki, P. (2001) “Deficient DNA mismatch repair: a common etiologic factor for colon cancer.” Human Molecular Genetics, 10, 735-740.