The Role of MSH2 in Hereditary Non-Polyposis Colon Cancer

Slides:



Advertisements
Similar presentations
Mismatch Repair Deficiency Testing Kenneth J. Bloom, MD, FCAP Chief Medical Officer, Clarient, a GE Healthcare Company.
Advertisements

Cancer: a genetic disease of inherited and somatic mutations n Gene mutations and/or genetic instability are involved in many cancers. n Viruses and environmental.
Lynch Syndrome and Colorectal Cancer Steven G. Proshan, M.D. Annapolis Colon and Rectal Surgeons Anne Arundel Medical Center November 8,
A few thoughts on cancer and cancer family syndromes Pamela McGrann, MD. Department of Medical Genetics.
COLORECTAL BLEEDING: a multidisciplinary approach Torino, 31 marzo-1 aprile 2006 GENETIC EVALUATION Schena M, Angelini F, Bertetto O. Department of Medical.
Lecture 22 Cancer Genetics II: Inherited Susceptibility to Cancer Stephen B. Gruber, MD, PhD November 19, 2002.
Mechanisms and Epidemiology of Colon Cancer
Hereditary Colorectal Cancer: An Overview Felice Schnoll-Sussman,MD Jay Monahan Center for Gastrointestinal Health New York Hospital/ Weill Cornell Medical.
Familial Colorectal Cancers Francis M. Giardiello, M.D. The Johns Hopkins University.
A signal transducer and cancer Neurofibromin, ras, and cancer - utah.
Morning Report May 20, 2009 Bridger Clarke  Born in Lawrence, Massachusetts, on 4 January  Dropped out of high school at the age of fourteen.
Chapter 8 Cancer Genetics.
Functional consequences of NLS mutations in human MLH1 Alex Dukes Dr. Andrew Buermeyer Department of Environmental & Molecular Toxicology Oregon State.
MMR & Hereditary Non-polyposis Colorectal Cancer
MLH 1 and Hereditary Nonpolyposis Colorectal Cancer
MSH2 and Human Nonpolyposis Colon Cancer Yael Aschner.
HNPCC and MLH1 Qi Peng Cancer Biology March 30 th, 2006.
Transforming Growth Factor β Receptor Type II Tina Morris
Determining Phenotypes of Pathogenic Mismatch Repair Mutants Brett Palama Lab of Andrew Buermeyer, Ph.D. Dept. of Environmental/Molecular Toxicology.
Copyright (c) by W. H. Freeman and Company Chapter 24 Cancer.
Pathogenic Mechanisms of Cancer Causing hMLH1 Mutations Functional Relationship between DNA Mismatch Repair and Tumor Formation Eddie O’Donnell Laboratory.
BRCA Genes Dallas Henson.
BRCA Mutations and Breast Cancer Ruth Phillips and Patty Ashby.
West Midlands Regional Genetics Laboratory
Immunohistochemistry (IHC) for Microsatellite Instability Fact Sheet Frequently Asked Questions What is Lynch Syndrome? Lynch syndrome is a hereditary.
Genetics & Colorectal Cancer
Gene Mutations.
DNA Repair and Cancer. Genome Instability Science, 26 July 2002, p. 544.
Cancer.
BRCA2 Clark Cunningham March 26, 2015 BIOL445 American Cancer Society, eastcancer/make-a-pink-ribbon-lapel-pin,
Angelina Jolie The White Coat Wonder. Rational  The purpose of our research is to enrich the Premed-A community with the knowledge of other cancers caused.
DNA Repair and Cancer Susceptibility
 FAP - familial adenomatous polyposis  germline mutations in the APC gene (“gatekeeper”)  HNPCC - hereditary nonpolyposis colon cancer (a.k.a. Lynch.
MLH1 & its role in Lynch Syndrome and sporadic colorectal cancers By Annie Jin.
Tumour Analysis-Lynch Syndrome Dr Alan Donaldson Consultant in Clinical Genetics Bristol.
Tumor Suppressors Versus Oncogenes. The Cancer Phenotype is Usually Recessive R. Weinberg, Cancer Biology.
סרטן מעי גס אבחון מוקדם מניעה טיפול מונע ד"ר הוברט אילה מנהלת המרכז לגידולים במערכת העיכול מכון שרת הדסה עין כרם.
Bonny Blackard Biology 169 April 4, 2006
MSH2 and Hereditary Nonpolyposis Colorectal Cancer By Bobby Glenn Warren III.
Natasha Adlakha Bio445. Discovery in Breast Cancer Reverse Genetics BReast CAncer Gene Chromosome 13 Tumor suppressor gene Penetrance Familial,
Tumor Suppressor Gene Involved in Breast and Ovarian Cancers SCIENCE96/gene.cgi?BRCA1.
TSC1/Hamartin and Facial Angiofibromas Biology 169 Ann Hau.
MLH1: Hereditary non- polyposis colon cancer (HNPCC) By: Alison Edge.
Have a positive role in cell division Have a negative role in cell division Have a role in the maintenance of DNA integrity Genes altered in cancer typically:
Chapter 11 Cancer Genetics. Cell responses to environmental signals.
Date of download: 5/31/2016 From: The Hereditary Nonpolyposis Colorectal Cancer Syndrome: Genetics and Clinical Implications[dhelix] Ann Intern Med. 2003;138(7):
HCDC4 & Endometrial Carcinoma Diana Rhyne. hCDC4 – Gene Information  Homologs in S. cervisiae, Drosophilia, and C. elegans  Tumor Suppressor  Expressed.
Lynch Syndrome or Hereditary Non-Polyposis Colorectal Cancer (HNPCC)
P57(KIP2) and Beckwith-Wiedemann Syndrome Shannon O’Leary.
MLH1 and HNPCC March 29, 2005 Tammy Jernigan
A Retrospective Analysis of Microsatellite Instability testing on colorectal cancer specimens in Queensland Public Hospitals Matthew Burge; Hayden Christie;
Genetics of Cancer Lecture 7
CANCER.
The Role of SMAD4 (DPC4) in Cancer
MLH1 Mutations and the Formation of Hereditary Non-Polyposis Colon Cancer(Lynch Syndrome) Kevin Harris Hereditary Non-polyposis Colorectal Cancer (HNPCC)
Tumor Promoting Inflammation
Concept 18.5: Cancer results from genetic changes that affect cell cycle control The gene regulation systems that go wrong during cancer are the very same.
Genomic Instability and Cancer
Genetics Of Cancer Regulation of cell proliferation and cancer
Colorectal cancer : Three pathways
PTEN (a.k.a. MMAC1 and TEP1) and Cowden’s Disease
The Role of Patch in Basal Cell Carcinoma
PTEN Tumor Suppressor and Cancer
BMP Receptor 1a and Juvenile Polyposis Syndrome
Noralane M Lindor  Clinical Gastroenterology and Hepatology 
A Knockout for Lynch Syndrome
Microsatellite Instability in Colorectal Cancer
Volume 128, Issue 5, Pages (May 2005)
Specific Tumor Suppressor Genes
A, Proportion of variants detected in the MMR genes.
Presentation transcript:

The Role of MSH2 in Hereditary Non-Polyposis Colon Cancer Joe McClellan Biol 445 Cancer Biology Spring 09

Hereditary Non-polyposis Colon Cancer 5-8% of all colon cancer Predisposition to colon cancer with very high penetrance HNPCC: 50-80% chance Normal: 5% chance Treatment: Full colectomy, followed by ileorectal anastomosis Still at risk for other cancers: endometrial, small intestine, ureter, renal pelvis Prognosis better with HNPCC than with sporadic colon cancer (Abdel-Rahman et al, 2006)

DNA Mismatch Repair Discovery of MSH2 Molecular role of MSH2 MSH2 in Colon Cancer

The DNA Mismatch Repair (MMR) System locates and repairs DNA replication errors Microsatellites: sequences made up of short, repeated sequences. Ex: AAAAAAAAAAAAA; CACACACACACACACA Microsatellite Instability (MSI): When these sequences are longer or shorter than normal.

The discovery of MSH2 in humans Mutant yeast lacking MMR HNPCC Patients Microsatellite Instability Cloning of human MSH2

MSH2 works with MSH3/MSH6 to locate replication errors MLH1 dimer binds MSH2 complex and recruits other MMR proteins Helleman et al. BMC Cancer 2006 6:201

MSH2 is a tumor suppressor gene Inherit one bad copy -Still functional MMR Loss of Heterozygosity -No MMR system MSH2 MSH2 MSH2 MSH2

Why Colon Cancer? Normal Colon epithelial cells responsive to TGF-β TGF-β regulates cell proliferation and differentiation (http://www.hbt.nl/infopages/index.asp?MODUS=fullarticle&infId=37)

TGF-β RII is mutated as a result of MMR inactivation Figure 12.28 The Biology of Cancer (© Garland Science 2007)

MSH2 knockout mice MSH2 deprived ES cells: Microsatellite Instability MSH2 deficient mice: viable, no major abnormalities, but highly susceptible to lymphoid tumors Human w/o MSH2  Colon cancer Mouse w/o MSH2  Lymphoid cancer!

Mouse TGF-β RII does not have poly-A microsatellite Gene more stable during replication, less likely to slip (Jacob and Praz, 2002)

Inherit a bad copy of MSH2 Loss of Heterozygosity (LOH) Inactivation of MMR Increased Mutation Rate (i.e. Microsatellite Instability) Frameshift Mutation in TGF-β RII Colon epithelial cells unable to respond to TGF- β Proliferation

References R. Fishel, M.K. Lescoe, M.R. Rao, N.G. Copeland, N.A. Jenkins, J. Garber, M. Kane, R. Kolodner, The human mutator gene homolog MSH2 and its association with hereditary nonpolyposis colon cancer, Cell 75 (1993) 1027–1038. S. Jacob and F. Praz. DNA mismatch repair defects: role in colorectal carcinogenesis, Biochimie 84 (2002), pp. 27–47. P. Peltomaki. Deficient DNA mismatch repair: a common etiologic factor for colon cancer. Human Molecular Genetics 10 (2001) : 735 2001 W. Kohlmann, S. B. Gruber. “Hereditary Non-Polyposis Colon Cancer.” Gene Reviews. (29 Nov. 2006). 1 March 2009 http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=gene&part=hnpcc S Y Koyama and D K Podolsky. Differential expression of transforming growth factors alpha and beta in rat intestinal epithelial cells. J. Clin. Invest. 83(5): 1768-1773 (1989). W.M. Abdel-Rahman, J.P. Mecklin and P. Peltomaki, The genetics of HNPCC: application to diagnosis and screening, Critical Reviews in Oncology–Hematology 58 (2006), pp. 208–220 V. Stigliano et al. Survival of hereditary non-polyposis colorectal cancer patients compared with sporadic colorectal cancer patients. J Exp Clin Cancer Res. 2008; 27(1): 39.