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.biomedcent ral.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. 2 nd 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/forsch ung_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/encyclopediaimag es/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 BiochimieBiochimie Volume 84, Issue 1, Jan 2002, Pg 33Volume 84, Issue 1

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

14. TGFB-R2 microsatellite instability Biochimie Biochimie Volume 84, Issue 1, Jan 2002, Pg 38lume 84, Issue 1

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=120436http://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 http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=120435 Genetics Home Reference. MLH1. http://ghr.nlm.nih.gov/gene=mlh1