Systems and The study of disease transmission of Colon Growth.


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Incendiary inside infection. Family history of CRC. Genetic colon ... ovary, stomach, urinary tract, little entrail, bile pipes, sebaceous skin tumors ...
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Systems and Epidemiology of Colon Cancer Anil K. Rustgi, MD University of Pennsylvania

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Worldwide Statistics for Colorectal Cancer (CRC) Estimated 875,000 cases in 1996  8.5% of all new instances of malignancy Incidence rates shift by ~20-fold  most elevated in North America, Western Europe, Australia, New Zealand, Japan  least in India, Northern Africa Estimated passings for 1998: 556,000

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Estimated New Cancer Cases of 10 Leading Sites by Gender for the US 2000

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Colorectal Cancer Statistics in the US Second general driving reason for growth related passings in the US Estimated 130,000 new cases and 56,300 passings in the year 2000 Declining patterns somewhere around 1990 and 1996 Incidence reate: ~2.1% every year Mortality rates: ~1.7% every year

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Average Annual Age-Specific US Incidence and Mortality Rates of CRC, 1992-1996

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Risk Factors for Colorectal Cancer (CRC) Aging Personal history of CRC or adenomas High-fat, low-fiber diet Inflammatory gut ailment Family history of CRC Hereditary colon tumor disorders

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Risk of Colorectal Cancer (CRC) 5% General populace Personal history of colorectal neoplasia 15%–20% Inflammatory gut ailment 15%–40% 70%–80% HNPCC transformation >95% FAP 0 20 40 60 80 100 Lifetime hazard (%)

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Familial Risk for Colorectal Cancer 70% Approximate lifetime CRC hazard (%) 17% 10% 8% 6% 2% One 1° and two 2° One 1° age <45 HNPCC change None One 1° Two 1° Aarnio M et al. Int J Cancer 64:430, 1995 Houlston RS et al. Br Med J 301:366, 1990 St John DJ et al. Ann Intern Med 118:785, 1993 Affected relatives

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Causes of Hereditary Susceptibility to CRC Sporadic (65 %– 85%) Familial (10 %– 30%) Rare CRC disorders (<0.1%) Hereditary nonpolyposis colorectal tumor (HNPCC) (5%) Familial adenomatous polyposis (FAP) (1%) Adapted from Burt RW et al. Anticipation and Early Detection of CRC , 1996

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Clinical Features of FAP Estimated penetrance for adenomas >90% Risk of extracolonic tumors (upper GI, desmoid, osteoma, thyroid, cerebrum, other) CHRPE might be available Untreated polyposis prompts 100% danger of disease

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Genetics of FAP Autosomal predominant legacy Caused by transformations in APC tumor silencer quality on chromosome 5q Up to 30% of patients have once more germline changes Most families have special transformations Most transformations are protein truncating Genotype/phenotype connections rising

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15 3 7 14 1 2 4 5 6 8 9 10 12 13 11 The APC Tumor Suppressor Gene Codon 1309 5\' 3\'

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Attenuated FAP Later onset (CRC ~age 50) Few colonic adenomas Not connected with CHRPE UGI injuries Associated with changes at 5 " and 3 " closures of APC quality

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Indications for APC Gene Testing Molecular determination of FAP in patients who present with: polyposis (>100 adenomas) constricted FAP Predictive testing for FAP in blood relatives of people with FAP or known APC transformations Giardiello FM et al. N Engl J Med , 336:823, 1997

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Early yet variable age at CRC finding (~45 years) Tumor site in proximal colon prevails Extracolonic diseases: endometrium, ovary, stomach, urinary tract, little gut, bile channels, sebaceous skin tumors Clinical Features of HNPCC

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Amsterdam Criteria 3 or more relatives with checked CRC in family One case a first-degree relative of the other Two or more eras One CRC by age 50 FAP rejected Failure to meet these criteria does not prohibit HNPCC Vasen HFA et al. Dis Colon Rect 34:424, 1991

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Genetic Features of HNPCC Autosomal predominant legacy Penetrance ~80% Genes have a place with DNA jumble repair (MMR) family Genetic heterogeneity ( MLH1, MSH2, MSH6, PMS1, PMS2 )

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Contribution of Gene Mutations to HNPCC Families Sporadic Familial Unknown ~30% MSH2 ~30% HNPCC Rare CRC disorders FAP MLH1 ~30% MSH6 (uncommon) PMS1 (uncommon) PMS2 (uncommon) Liu B et al. Nat Med 2:169, 1996

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Cancer Risks in HNPCC 100 80 % with disease Colorectal 78% 60 Endometrial 43% 40 Stomach 19% 20 Biliary tract 18% Urinary tract 10% Ovarian 9% 0 20 40 60 80 Age (years) Aarnio M et al. Int J Cancer 64:430, 1995

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Microsatellite Instability (MSI) 10%–15% of sporadic tumors have MSI 95% of HNPCC tumors have MSI at various loci Routine MSI examines soon accessible Normal MSI tumor Electrophoresis gel

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Genetic Testing for HNPCC Susceptibility Begin hereditary testing with influenced relative Positive result Negative result Continued danger of unidentified familial transformation Offer testing to at-danger relatives

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Features of Familial CRC Family history of CRC with no reasonable legacy design Age at onset common of sporadic CRC Multiple causes Few or no adenomas Sporadic Familial CRC FAP HNPCC Rare CRC disorders

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Mouse Models of Colon Cancer Apc (Min) Smad DNA confuse repair Ras

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Loss of APC Activation of K-ras Deletion of 18q Loss of TP53 Other changes Normal epithelium Hyper-proliferative epithelium Early adenoma Inter-intercede adenoma Late adenoma Carcinoma Metastasis Adapted from Fearon ER. Cell 61:759, 1990

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Adenomatous polyp Adenomatous polyp Can take 5-10 years for polyp to create Up to 10% of polyps form into growth Size and histology are danger components for polyp to tumor movement

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Surrogate Markers for Chemoprevention Polyp (size/number) Mouse models, FAP/HNPCC, General populace (sporadic) Biomarkers (mucosa/polyp) Proliferation Differentiation Apoptosis Gene exhibits (useful genomics) Biomarkers (stool/blood) Investigational

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Summary Risk elements for colon disease Inherited Acquired (sporadic)- adenomatous polyp, IBD Genetic premise for colon malignancy Inherited (FAP, HNPCC, to be characterized) Sporadic polyp-diverse pathways Preclinical models for colon disease

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Summary (proceeded with) Applications of chemoprevention at first in creature models and acquired types of colon growth, and afterward to overall public Determine adequacy of chemoprevention with surrogate markers

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