MLH1: Hereditary non-polyposis colon cancer (HNPCC)

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MLH1 Hereditary non-polyposis colon cancer
(HNPCC)

• By Alison Edge

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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
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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

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DNA MMR system
http//www.biomedcentral.com/1471-2407/6/201/
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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/MLH1
Fig2.jpg
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What happens when there is a deficiency in MLH1?

• Microsatellite instability
• Increase in base-base mismatches
• Frameshift mutations

http//www.jewishgeneticscenter.org/images/mismatc
h2.gif
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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/mlh
1.jpeg
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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

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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/Uniklin
ik_Homburg/Kliniken/Gastroenterologie/Forschung/fo
rschung_mmr.jpg
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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/encyclo
pediaimages/a/au/autosomal_dominant_pedigree_chart
.svg.png
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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

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MLH1 and HNPCC

• 200 different mutations of MLH1
• Most mutations found near exons 15 and 16

Biochimie Volume 84, Issue 1, Jan 2002, Pg 33
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Mutations in MLH1 associated with HNPCC
http//www.jewishgeneticscenter.org/images/fig2.gi
f
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TGFB-R2 microsatellite instability
BiochimieVolume 84, Issue 1, Jan 2002, Pg 38
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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

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Summary

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

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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 OBrien, 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?id120436
• Online Mendelian Inheritance in Man. Lynch
  Syndrome I. http//www.ncbi.nlm.nih.gov/entrez/dis
  pomim.cgi?id120435
• Genetics Home Reference. MLH1. http//ghr.nlm.nih.
  gov/genemlh1