癌症世界难题.ppt

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1、Genetics and Primary Care,Familial Cancer Risk AssessmentColorectal Cancer,Case 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 pol

2、yps removed No other significant history Both sides of the family are Northern European Caucasian,http:/龙门吊 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

3、 grandfather: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&34Maternal grandmother:breast cancer age 85,Outline,Hereditary colorectal cancer syndromesCancer family history a primary toolEva

4、luating your patients for familial CRC riskGenetic counseling and testing for hereditary colorectal cancerHow,when,where to refer patients for genetic services,Colorectal Cancer,5-8%of all cases of CRC are hereditary15-20%are“familial”/multifactorial75%of cases are sporadicFeuer EJ:DEVCAN:National C

5、A Inst.1999,Characteristics of Average Risk,No 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 CRC,Characte

6、ristics 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

7、at playFamily members warrant earlier CRC screeningStarting at 40 years or 5-10 yrs earlier than age of diagnosis of the youngest affected relative,Winawer et al.,Gastroenterology 2003:124:544-560,Characteristics of Hereditary CRC,Multiple relatives with colorectal cancerOne or more diagnosed at an

8、early age(50)Sequential generations affectedExcept in autosomal recessive syndromesOther cancers in the family known to be associated with CRC(uterine,ovarian,GI)Multiple primary tumors or polyps,Hereditary CRC syndromes,Hereditary Non-Polyposis Colorectal Cancer(HNPCC)Variants:Muir-Torre,TurcotFami

9、lial Adenomatous 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 Cancer,In the typical primary care practice,2 to 8 patient

10、s(1/200 to 1/800)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;h

11、igh penetranceTypical 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,HNPCC,Lifetime cancer risks:Colorectal 80%Endometrial 20-60%Gastric 13-19%Ovarian 9-12%Biliary tract 2%Urinary tra

12、ct 4%Small bowel 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 50,HNPCC,Cause

13、d by mutations or deletions 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 tum

14、or tissue by MSI/IHC,Proceed Directly To Genetic Testing After genetic counseling and informed consent!,IF:Family history fulfills Amsterdam II criteria orPatient has two HNPCC related cancers orPatient has CRC and a 1st degree relative with HNPCC-related cancer,with at least one cancer diagnosed 50

15、 years of ageAlways test an affected family member first!,MSI/IHC screening,Microsatellite 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,et

16、c.)“Screen positive”individuals can be offered cancer genetic counseling/assessment and targeted genetic testing,Criteria for MSI/IHC screening,Revised Bethesda Criteria,2004CRC or endometrial CA 50 yrs2 HNPCC cancers in same personCRC with“MSI-H histology”diagnosed 60 yrsInfiltrating lymphocytes,Cr

17、ohns-like lymphocytic reaction,mucinous/signet ring differentiation,medullary growth patternCRC and one or more 1st degree relative with an HNPCC-related cancer,one diagnosed 50 yrsCRC and two or more 1st or 2nd degree relatives with HNPCC-related cancers,any age,Umar A et al:J Natl Cancer Inst,2004

18、;96(4):261-268,HNPCC Surveillance,Gene carriers or at-risk relatives:CRC:colonoscopy age 20-25,repeat 1-2 yrsWomen:gyn exam,endometrial aspiration,TV U/S,CA-125(?)age 25-35,repeat 1-2 yrsIf one HNPCC family member affected w/the following:Stomach CA:EGD age 3-35,repeat 1-2 yrsUrinary tract CA:urine

19、cytology age 30-35,repeat 1-2 yrs,NCCN practice guidelines in oncology v.1.2003,FAP,1 in 10,000 incidence 100s to 1000s of colonic adenomas by teensCancer risk:colon,gastric,duodenum(periampulla),small bowel,pancreas,papillary thyroid,childhood hepatoblastoma7%risk of CRC by 21 yrs;93%by 50 yrsAutos

20、omal dominant:APC gene mutationsVariants:Gardner,Turcot,FAP surveillance,ColonAnnual sigmoidoscopy,age 10-12 yrsProphylactic colectomy following polyp detection w/continued surveillance of rectum,ileal pouchDuodenal/gastric EGD age 25,repeat 1-3 yrsThyroid Annual PE,age 10Hepatoblastoma Annual scree

21、n by abd U/S&AFP from birth to 5 yrs.,Gastroenterology 2001;121:195.AGA Statement,Attenuated FAP,20 to 100 polyps,usually more proximalOnset later than FAP,average AOO=50Lifetime risk of CRC=80%Extracolonic tumors occur at same rate as FAPVariant of FAP,mutations in same APC geneSurveillance:annual

22、colonoscopy starting late teens or early 20s Option of subtotal colectomy,Genetic Testing:FAP/AFAP,Test an affected family member first!After genetic counseling and informed consentAPC gene testing can confirm a suspected diagnosisFamily members of a person with a known APC mutation can have mutatio

23、n-specific testing Genetic testing for children at risk for FAP can be considered before beginning colon screening,APC gene mutation in Ashkenazi Jews,Missense mutation(I1307K)associated with increased risk of CRC and adenomas in Ashkenazi Jews(AJ)Found in 6%of the general AJ population12%of AJs wit

24、h CRC 29%of AJs with CRC and a positive family history Lifetime risk of CRC in mutation carrier is 10-20%Screening:colonscopy every 2-5 yrs starting at 35 yrs,MAP syndrome/MYH gene,Multiple adenomatous polyposis(MAP)syndromeAutosomal recessive;mutations in the MYH geneMedian number of polyps=55 Mean

25、 age of polyp diagnosis=30-50 yearsPolyps mainly small,mildly dysplastic tubular adenomas.Some tubulovillous,hyperplastic,serrated adenomas,microadenomas30%of individuals with 15-100 polyps have homozygous mutations in the MYH geneGenetic testing should be offered if 15 polyps(and APC gene testing negative),