Hereditary qualities of Colorectal Growth.

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Assessed New Cancer Cases of 10 Leading Sites by Gender for the US 2000 ...
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Hereditary qualities of Colorectal Cancer

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Cancer is a Disease of the Cell Cycle "Carcinoma is a hereditary ailment, it is not as a matter of course acquired"

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Knudsen\'s "two hit" theory

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Types of qualities which may transform to bring about growth: Oncogenes Suppressor qualities DNA repair qualities p53

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Adenoma-Carcinoma Sequence Accumulation of Mutations DCC, MCC, p53, K-ras, APC, MSH2, MLH1, and so forth

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

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

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Prevalence of Adenomas and Incidence of Colon Cancer Age > 50 years with any adenomas: 25-40% Lifetime danger of malignancy at age 50 years 5% for females 6% for guys Persons with cutting edge adenomas are at most serious danger

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

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Risk of Colorectal Cancer (CRC) 5% General Population Personal History of Colorectal Neoplasia 15-20% 15-40% Inflammatory Bowel Disease 70-80% HNPCC Mutation >95% Familial Adenomatous Polyposis (FAP) Lifetime Risk (%)

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Colorectal Cancer Statistics in the US Second general driving reason for malignancy related passings in the U.S. Assessed 149,000 new cases and 50,000 passings in the year 2008 Declining patterns somewhere around 1990 and 1996 Incidence rate: ~2.1% every year Mortality rates: ~1.7% every year

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Family History: Empiric Risks

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Outline Hereditary colorectal malignancy disorders Cancer family history – an essential instrument Evaluating your patients for familial CRC hazard Genetic advising and testing for innate colorectal growth How, when, where to allude patients for hereditary administrations

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Colorectal Cancer ~5-8% of all instances of CRC are inherited ~15-20% are "familial"/multifactorial ~75% of cases are sporadic

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Characteristics of Average Risk No all around characterized limit amongst sporadic and familial CRC as of now Probably safe to incorporate people with: No individual danger components or family history of CRC One 2 nd or 3 rd degree relative with CRC >60 years with no other family history of CRC

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Characteristics of "Familial" CRC "Bunching" of colon disease cases in the family (>50 at conclusion) without clear predominant example, or One close relative with CRC <60 years and family history does not meet criteria for known innate CRC disorders Likely to be numerous low penetrant qualities in addition to ecological variables at play Family individuals warrant prior CRC screening Starting at 40 years or 5-10 years sooner than period of analysis of the most youthful influenced relative

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Characteristics of Hereditary CRC Multiple relatives with colorectal growth One or more analyzed at an early age (<50) Sequential eras influenced Except in autosomal latent disorders Other malignancies in the family known not connected with CRC (uterine, ovarian, GI) Multiple essential tumors or polyps

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Hereditary CRC Syndromes Hereditary Non-Polyposis Colorectal Cancer (HNPCC) Variants: Muir-Torre, Turcot Familial Adenomatous Polyposis (FAP) Variants: Gardner, Turcot Attenuated FAP APC transformation in Ashkenazi Jews Others: Multiple adenomatous polyposis disorder/MYH quality (MAP) Peutz-Jeghers disorder (PJS) Familial Juvenile Polyposis (FJP)

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HNPCC: AKA "Lynch Syndrome" 2-3% of all colorectal tumor cases Autosomal overwhelming; high penetrance Typical time of CA onset is 40-50 years Multiple influenced eras 60-70% right-sided/proximal CRC tumors Polyps might be available, various primaries basic. Can cover with AFAP.

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HNPCC Lifetime disease dangers: Colorectal 80% Endometrial 20-60% Gastric 13-19% Ovarian 9-12% Biliary Tract 2% Urinary Tract 4% Small Bowel 1-4% Brain/CNS 1-3%

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HNPCC: Clinical Diagnostic Criteria Amsterdam II Criteria (3-2-1) 3 or more relatives with a HNPCC-related malignancy, one of whom is a 1 st degree relative of the other two 2 or more progressive eras influenced 1 or more growths analyzed before age 50

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HNPCC Caused by changes or cancellations in befuddled repair (MMR) qualities MSH2, MLH1, MSH6, (PMS2) half of families meeting Amsterdam II Criteria have noticeable transformations Testing/Screening alternatives: Direct hereditary testing of MMR qualities (in select families) Initial screening of the tumor tissue by MSI/IHC

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MSI/IHC Screening Microsatellite Instability (MSI) on tumor tissue can be utilized to screen for HNPCC in select cases Immunohistochemistry (IHC) on tumor tissue can be utilized to identify the nearness or nonattendance of the confound repair proteins (MSH2, MLH1, and so forth.) " Screen positive " people can be offered growth hereditary guiding/appraisal and focused on hereditary testing

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FAP 1 in 10,000 occurrence 100\'s to 1000\'s of colonic adenomas by high schoolers Cancer hazard: colon, gastric, duodenum (periampulla), little gut, pancreas, papillary thyroid, youth hepatoblastoma 7% danger of CRC by 21 yrs; 93% by 50 yrs Autosomal prevailing: APC quality transformations Variants: Gardner, Turcot

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FAP - Surveillance Colon Annual sigmoidoscopy, age 10-12 yrs Prophylactic colectomy taking after polyp identification with proceeded with reconnaissance of rectum, ileal pocket Duodenal/gastric EGD age 25, rehash 1-3 yrs Thyroid Annual PE, age 10 Hepatoblastoma Annual screen by abd U/S & AFP from birth to 5 yrs.

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Attenuated FAP 20 to 100 polyps, typically more proximal Onset later than FAP, normal AOO = 50 Lifetime danger of CRC = 80% Extracolonic tumors happen at same rate as FAP Variant of FAP, transformations in same APC quality Surveillance: yearly colonoscopy beginning late youngsters or mid 20\'s Option of subtotal colectomy

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Genetic Testing: FAP/AFAP Test an influenced relative first! After hereditary directing and educated assent APC quality testing can affirm an associated conclusion Family individuals with a man with a known APC change can have transformation particular testing Genetic testing for kids at danger for FAP can be considered before starting colon screening

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APC quality change in Ashkenazi Jews Missense change (I1307K) connected with expanded danger of CRC and adenomas in Ashkenazi Jews (AJ) Found in 6% of the general AJ populace 12% of AJs with CRC 29% of AJs with CRC and a positive family history Lifetime danger of CRC in change transporter is 10-20% Screening: colonoscopy each 2-5 yrs beginning at 35 yrs

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MAP disorder/MYH quality Multiple adenomatous polyposis (MAP) disorder Autosomal latent; changes in the MYH quality Median number of polyps = 55 Mean period of polyp determination = 30-50 years Polyps basically little, somewhat dysplastic tubular adenomas. Some tubulovillous, hyperplastic, serrated adenomas, microadenomas 30% of people with 15-100 polyps have homozygous transformations in the MYH quality Genetic testing ought to be offered if >15 polyps (and APC quality testing pessimistic)

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Peutz-Jeghers Syndrome <1% of all CRC cases Hamartomatous polyps of GI tract as ahead of schedule as 1 st decade Mucocutaneous hyper pigmentation lips, mouth, buccal mucosa, fingers Usually found in kids < 5 yrs Cancer hazard: colon, small digestive system, stomach, pancreas, bosom, ovaries, uterus, testicles, lungs, kidneys Mutations in STK11 quality found in 70% of familial cases and 30-70% of sporadic cases

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Familial Juvenile Polyposis <1% of all CRC cases Autosomal prevailing 5 or more adolescent polyps in colon or GI tract Appear in 1 st or 2 nd decade half lifetime danger of CRC; AOO in 30\'s Increased danger gastric, GI, pancreatic CA ~50% of cases have changes in either the MADH4 or BMPR1A qualities

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Family Health History "The family tree has turned into the most vital hereditary trial of all. The more you know, the more devices you need to practice preventive prescription" ** Donna Russo, Certified Genetic Counselor, NY Presbyterian-Columbia Hospital

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Goal: Classification Assessment Risk Classification Intervention Standard avoidance suggestions Average Family History Moderate ("Familial") Personalized aversion proposals Referral for hereditary assessment with customized counteractive action proposals High/Genetic

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Consider Genetics Referral for: Two or all the more relatives with CRC* no less than one <50 Three or all the more relatives w/CRC*; any age Patient with colon disease before 40 yrs Endometrial malignancy and family history of CRC <50 Persons with more than one essential CRC <50 yrs or with both endometrial CA and CRC Family or individual history of CRC and one or more 1 st degree relative with a HNPCC-related tumor, one analyzed <50 yrs. * Same side of family

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Consider Genetics Referral for: MSI and/or IHC tumor results suspicious for HNPCC Autosomal prevailing example of malignancies in the family Persons with 15 or more adenomatous colorectal polyps Persons with various hamartomatous or adolescent GI polyps Persons with a family history of a known inherited growth disorder

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CRC Risk Management Average Risk No family history CRC OR One 2 nd or 3 rd degree relative with CRC FOBT every year + flex sig at regular intervals; OR Colonoscopy at regular intervals; OR DCBE at regular intervals Age to Begin 50 years

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CRC Risk Management Moderate/Family history Two first degree relatives with CRC any age or one first degree relative with CRC < 60 -Colonoscopy each 5 yrs One first degree relative with CRC >60 or two second degree relatives with CRC any age -Average danger screening * Or 5-10 yrs sooner than most punctual case in family Age to start 40 years* 40 years

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CRC Risk Management Age to Begin HNPCC or suspected HNPCC 20-25 years 1. Co