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MSH2 and Hereditary Nonpolyposis Colon Cancer

MSH2 and Hereditary Nonpolyposis Colon Cancer. Keri Nakao 5 April 2005. Hereditary Nonpolyposis Colorectal Cancer. Tumors on proximal (right side) colon Tumors in gastrointestinal tract and genitourinary tract often Muir-Torre. http://ghr.nlm.nih.gov/gene=msh2. MSH2 located on Chromosome 2.

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MSH2 and Hereditary Nonpolyposis Colon Cancer

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  1. MSH2 and Hereditary Nonpolyposis Colon Cancer Keri Nakao 5 April 2005

  2. Hereditary Nonpolyposis Colorectal Cancer • Tumors on proximal (right side) colon • Tumors in gastrointestinal tract and genitourinary tract often • Muir-Torre http://ghr.nlm.nih.gov/gene=msh2

  3. MSH2 located on Chromosome 2 Location – 2p22-p21 Cell. 1993 Dec 3;75(5):1027-38. Fishel et al. k-12.pisd.edu/.../ Genetic/Chromosome-02.htm

  4. Mismatch Repair System • MSH2 and MSH6 bind to mismatched segment of DNA • DNA helicase unwinds helix • MLH1 endonuclease binds to complex and excises replication error • DNA polymerase fills gap • DNA ligase Lodish et al. Fig. 23-28

  5. Insertion-Deletion Loops www.sci.sdsu.edu/.../ mutations/deletions.html

  6. MSH2 Gene Mapping genome.chmcc.org/.../ SNProtein/Polydom.html

  7. MSH2 Structure Cell. 1997 Dec 26;91(7):995-1005. Gradia et al.

  8. Knockout Mice MSH2 -/- Nature Genetics. 1995 Sep;11(1):64-70. Reitmair et al. Cell. 1995 Jul 28;82(2):321-30. de Wind et al.

  9. Knockouts tolerant to MNNG • MNNG induces: • chromosomal aberrations • Sister chromosome exchanges • DNA strand breaks • Unscheduled DNA synthesis www.uoguelph.ca/.../ 4426/Mutagenesis6.html http://monographs.iarc.fr/htdocs/monographs/suppl7/mnng.html

  10. HNPCC www.healingdaily.com/.../ colon-health.htm

  11. Mutations in MSH2 • Deletions in poly(dA/dT) sequences and other simple repeats • Frameshifts or point mutations that result in STOP codons • Missense American Journal of Human Genetics. 1995 May;56(5):1060-6. Wijnen et al. Human Genetics. 1996 Feb;97(2):251-5. Maliaka et al.

  12. Treatment • Family testing • Risk is significantly higher in males • Aspirin or Suldinac Proceedings of the National Academy of Science of the U S A. 1998 Sep 15;95(19):11301-6. Ruschoff et al.

  13. Summary • Mismatch Repair System • Knockout mice viable but develop lymphomas • Many mutations in MSH2 may cause HNPCC

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