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MLH1: Hereditary non-polyposis colon cancer (HNPCC)

MLH1: Hereditary non-polyposis colon cancer (HNPCC). By: Alison Edge. Normal MLH1 Function. Makes a protein that plays an essential role in DNA mismatch repair system (MMR). Human Molecular Genetics, 2001, Vol. 10, No. 7 pg 736. Functions of MMR System. Post replication repair

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MLH1: Hereditary non-polyposis colon cancer (HNPCC)

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  1. MLH1: Hereditary non-polyposis colon cancer (HNPCC) By: Alison Edge

  2. Normal MLH1 Function • Makes a protein that plays an essential role in DNA mismatch repair system (MMR) Human Molecular Genetics, 2001, Vol. 10, No. 7 pg 736

  3. Functions of MMR System • Post replication repair • Cell cycle regulation and apoptotic response • Prevents recombination between diverged sequences to promote genetic stability • Recognizes DNA adducts caused by alkylating agents or heterocyclic amines and initiates apoptosis

  4. DNA MMR system http://www.biomedcentral.com/1471-2407/6/201/

  5. Facts about MLH1 gene • On short arm of chromosome 3 at position 21.3 • Has 19 exons and encodes a 756 amino acid protein http://atlasgeneticsoncology.org/Genes/Images/MLH1Fig2.jpg

  6. What happens when there is a deficiency in MLH1? • Microsatellite instability • Increase in base-base mismatches • Frameshift mutations http://www.jewishgeneticscenter.org/images/mismatch2.gif

  7. First evidence of MLH1 in tumors • Dr. Lynch studied families with adenocarcinomas of the colon, endometrium and stomach • Identified LOH by using unstable microsatellites MSH2 homolog of MutS MLH1 homolog of MutL http://ghr.nlm.nih.gov/dynamicImages/chromomap/mlh1.jpeg

  8. Animal Models to determine MLH1 function • Generated mice with null mutation in MLH1 • Sterility • Cell cycle arrest in first division of meiosis • Concluded MLH1 in mouse is involved in DNA MMR and meiotic crossing over

  9. 2nd Mouse study for MLH1 • Avdievich generated transgenic mice with a G67R mutation in MLH1 gene in 1 of ATP binding domains http://www.uniklinikum-saarland.de/mediadb/Uniklinik_Homburg/Kliniken/Gastroenterologie/Forschung/forschung_mmr.jpg

  10. Facts about HNPCC • Most common form of hereditary colon cancer Autosomal dominantly inherited • Results from deficient DNA mismatch repair • Tumors have microsatellite instability • Cancer arises from germline mutations in either MMR gene MLH1 or MSH2 • Sporadic cases of cancer are caused by hypermethylation of MLH1 promoter http://images.absoluteastronomy.com/images/encyclopediaimages/a/au/autosomal_dominant_pedigree_chart.svg.png

  11. 2 types of HNPCC • HNPCC subdivided into Lynch syndrome I or Lynch syndrome II • Lynch syndrome I is site specific colonic cancer • Lynch syndrome II is extracolonic cancer • Carcinoma of the stomach, endometrium, biliary and pancreatic system, and urinary tract

  12. MLH1 and HNPCC • 200 different mutations of MLH1 • Most mutations found near exons 15 and 16 BiochimieVolume 84, Issue 1, Jan 2002, Pg 33

  13. Mutations in MLH1 associated with HNPCC http://www.jewishgeneticscenter.org/images/fig2.gif

  14. TGFB-R2 microsatellite instability BiochimieVolume 84, Issue 1, Jan 2002, Pg 38

  15. Detection and Prevention • Colonoscopy at age 25 • Antibodies for MSH2 and MLH1led to immunohistochemistry surrogate test for detection of MSI • Nonsteroidal antiinflammatory drugs used as cancer preventive because have antiproliferative and apoptosis inducing activiites

  16. Summary • Inherit mutation in MLH1 gene • LOH to lose wild type MLH1 gene • Deficient DNA MMR system • Mutated TGFB-R2 from microsatellite instability • HNPCC

  17. References • Deficient DNA mismatch repair: a common etiologic factor for colon cancer. Human Molecular Genetics, 2001, Vol. 10, No.7: pgs 735-740. • Sandrine Jacob, Francoise Praz. DNA mismatch repair defects: role in colorectal carcinogenesis. Biochimie, 2002, Vol. 84: pgs 27-47. • J G Stone, D Robertson, R S Houlston. Immunohistochemistry for MSH2 and MLH1: a method for identifying mismatch repair deficient colorectal cancer. F Clin Pathol, 2001, Vol. 54: pgs 484-487. • Vincent O’Brien, Robert Brown. Signaling cell cycle arrest and cell death through the MMR system. Carcinogenesis, 2006, Vol. 27, No.4: pgs 682-692. • Online Mendelian Inheritance in Man. MutL, E. COLI, Homolog of, 1; MLH1. http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=120436 • Online Mendelian Inheritance in Man. Lynch Syndrome I. http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=120435 • Genetics Home Reference. MLH1. http://ghr.nlm.nih.gov/gene=mlh1

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