Download MLH1: Hereditary non-polyposis colon cancer (HNPCC)

MLH1: Hereditary nonpolyposis colon cancer
(HNPCC)
By: Alison Edge
Normal MLH1 Function
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Makes a protein that plays an essential role
in DNA mismatch repair system (MMR)
Functions of MMR System
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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
DNA MMR system
http://www.biomedcent
ral.com/14712407/6/201/
Facts about MLH1 gene
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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
What happens when there is a
deficiency in MLH1?
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Microsatellite instability
Increase in base-base mismatches
Frameshift mutations
http://www.jewishgeneticscenter.org/images/mismatch2.gif
First evidence of MLH1 in tumors
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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
Animal Models to determine MLH1
function
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Generated mice with null mutation in MLH1
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Sterility
Cell cycle arrest in first division of meiosis
Concluded MLH1 in mouse is involved in DNA
MMR and meiotic crossing over
2nd Mouse study for MLH1
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Avdievich generated transgenic mice with a G67R
mutation in MLH1 gene in 1 of ATP binding domains
http://www.uniklinikumsaarland.de/mediadb/Uniklinik_Homburg/Kliniken/Gastroenterologie/Forschung/forsch
Facts about HNPCC
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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
2 types of HNPCC
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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
MLH1 and HNPCC
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200 different mutations of MLH1
Most mutations found near exons 15 and 16
Biochimie Volume 84, Issue 1, Jan 2002, Pg 33
Mutations in MLH1 associated with
HNPCC
http://www.jewishgeneticscenter.org/images/fig2.gif
TGFB-R2 microsatellite instability
Biochimie
Volume 84, Issue 1, Jan 2002, Pg 38
Detection and Prevention
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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
Summary
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Inherit mutation in MLH1 gene
LOH to lose wild type MLH1 gene
Deficient DNA MMR system
Mutated TGFB-R2 from microsatellite
instability
HNPCC
References
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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