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1、Genetics and Primary CareFamilial Cancer Risk AssessmentColorectal CancerCase 1:Joan Joan,age 38,was recently diagnosed with endometrial cancer.Family history reveals:Paternal grandmother:endometrial cancer,age 50 Paternal uncle:colon cancer,age 48 Father:colonoscopy at age 50;four adenomatous polyp
2、s removed No other significant history Both sides of the family are Northern European Caucasianhttp:/ 单梁起重机 大连渤海起重 http:/ http:/ Case 2:Ted Ted is 30 and wants a colonoscopy because his mother was just diagnosed with colon cancer after routine screening at age 54.Family history reveals:Paternal gran
3、dfather:died of CRC at age 79 No hx of endometrial,ovarian,small bowel or ureter/kidney cancer on either side of family Two maternal aunts:cervical cancer at ages 30&34 Maternal grandmother:breast cancer age 85 OutlineHereditary colorectal cancer syndromesCancer family history a primary toolEvaluati
4、ng your patients for familial CRC riskGenetic counseling and testing for hereditary colorectal cancerHow,when,where to refer patients for genetic servicesColorectal Cancer 5-8%of all cases of CRC are hereditary15-20%are“familial”/multifactorial75%of cases are sporadicFeuer EJ:DEVCAN:National CA Inst
5、.1999 Characteristics of Average RiskNo well-defined threshold between sporadic and familial CRC at this timeProbably safe to include individuals with:No personal risk factors or family history of CRCOne 2nd or 3rd degree relative with CRC 60 years with no other family history of CRCCharacteristics
6、of“Familial”CRC“Clustering”of colon cancer cases in the family(50 at diagnosis)without clear dominant pattern,orOne close relative with CRC 60 yrs and family history does not meet criteria for known hereditary CRC syndromesLikely to be multiple low pentrant genes plus environmental factors at playFa
7、mily members warrant earlier CRC screeningStarting at 40 years or 5-10 yrs earlier than age of diagnosis of the youngest affected relativeWinawer et al.,Gastroenterology 2003:124:544-560Characteristics of Hereditary CRCMultiple relatives with colorectal cancerOne or more diagnosed at an early age(50
8、)Sequential generations affectedExcept in autosomal recessive syndromesOther cancers in the family known to be associated with CRC(uterine,ovarian,GI)Multiple primary tumors or polypsHereditary CRC syndromesHereditary Non-Polyposis Colorectal Cancer (HNPCC)Variants:Muir-Torre,TurcotFamilial Adenomat
9、ous Polyposis (FAP)Variants:Gardner,TurcotAttenuated FAP APC mutation in Ashkenazi JewsOthers:Multiple adenomatous polyposis syndrome/MYH gene(MAP)Peutz-Jeghers syndrome(PJS)Familial Juvenile Polyposis(FJP)In Your Practice:Colon CancerIn the typical primary care practice,2 to 8 patients(1/200 to 1/8
10、00)are from“high risk”families,with a condition called Hereditary Non-Polyposis Colon Cancer(HNPCC).These patients have a high lifetime risk of colorectal and other cancers with risk starting in their 20s.HNPCC:AKA“Lynch syndrome”2-3%of all colorectal cancer casesAutosomal dominant;high penetranceTy
11、pical age of CA onset is 40-50 yrsMultiple affected generations60-70%right-sided/proximal CRC tumorsPolyps may be present,multiple primaries common.Can overlap with AFAP HNPCCLifetime cancer risks:Colorectal 80%Endometrial 20-60%Gastric 13-19%Ovarian 9-12%Biliary tract 2%Urinary tract 4%Small bowel
12、1-4%Brain/CNS 1-3%HNPCC:Clinical Diagnostic Criteria Amsterdam II Criteria(3-2-1 rule)3 or more relatives with an HNPCC-related cancer,one of whom is a 1st degree relative of the other two2 or more successive generations affected1 or more cancers diagnosed before age 50HNPCC Caused by mutations or d
13、eletions in mismatch repair(MMR)genes MSH2,MLH1,MSH6,(PMS2)90%of detectable mutations in MSH2 and MLH150%of families meeting Amsterdam II Criteria have detectable mutationsTesting/screening options:Direct genetic testing of MMR genes(in select families)Initial screening of the tumor tissue by MSI/IH
14、C Proceed Directly To Genetic Testing After genetic counseling and informed consent!IF:Family history fulfills Amsterdam II criteria or Patient has two HNPCC related cancers or Patient has CRC and a 1st degree relative with HNPCC-related cancer,with at least one cancer diagnosed 50 years of age Alwa
15、ys test an affected family member first!MSI/IHC screeningMicrosatellite Instability(MSI)on tumor tissuecan be used to screen for HNPCC in select cases Immunohistochemistry(IHC)on tumor tissuecan be used to detect the presence or absence of the mismatch repair proteins(MSH2,MLH1,etc.)“Screen positive
16、”individuals can be offered cancer genetic counseling/assessment and targeted genetic testingCriteria for MSI/IHC screeningRevised Bethesda Criteria,2004 CRC or endometrial CA 50 yrs 2 HNPCC cancers in same person CRC with“MSI-H histology”diagnosed 60 yrs Infiltrating lymphocytes,Crohns-like lymphocytic reaction,mucinous/signet ring differentiation,medullary growth pattern CRC and one or more 1st degree relative with an HNPCC-related cancer,one diagnosed 15 polyps(and APC gene testing negative)
