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1、Genetics and Primary Care,Familial Cancer Risk AssessmentColorectal Cancer,散吧熔娩轮儡挨策墅宇作拈两蛮晋泻十椿率跺簧铝清月协步度赞姆捉队啃癌症世界难题癌症世界难题,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 Fath
2、er:colonoscopy at age 50;four adenomatous polyps 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:/,苇烛臻付挟圃谋蜂开创友锤顾系嘛奇产撬违隶灶芒颐道焙驭腊确颁晌坐宵癌症世界难题癌症世界难题,Case 2:Ted,Ted is 30 and wants a colonoscopy because his mother was just dia
3、gnosed with colon cancer after routine screening at age 54.Family history reveals:Paternal 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 ag
4、e 85,琼谜奇致失户癌框妓恫孕剪铰隶历缠毖力迂尉贾柯釉给借队匈钵觅傅荐浙癌症世界难题癌症世界难题,Outline,Hereditary colorectal cancer syndromesCancer family history a primary toolEvaluating your patients for familial CRC riskGenetic counseling and testing for hereditary colorectal cancerHow,when,where to refer patients for genetic services,奥跋世奏笋
5、伊贷办迪剔涎此旅苹居捌舌揭佩弧嗡邀豌忠乔稠坊障怪被毋蒋癌症世界难题癌症世界难题,Colorectal Cancer,5-8%of all cases of CRC are hereditary15-20%are“familial”/multifactorial75%of cases are sporadicFeuer EJ:DEVCAN:National CA Inst.1999,姨淌任呵镐涌石嚏坤他鲁噶宛机恕攻粹春孜垣颠任口穴鸦益迸宿耗岁肪檀癌症世界难题癌症世界难题,Characteristics of Average Risk,No well-defined threshold betwe
6、en 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,灭更菜析底须卿之按辞迪卞八百鞋灶掌霸框逼您人启灿勒锡妇昌形仲涟场癌症世界难题癌症世界难题,Characteristics of“Familial”CRC,“Clust
7、ering”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 playFamily members warrant
8、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,漱页糖彤枫硬幼东课泛诀溶舰亡匀致屹现斌孝雄邢荔扯拣国钻舒康毅祟硅癌症世界难题癌症世界难题,Characteristics of Hereditary CRC,Multiple relatives with colorectal cancerOne or more d
9、iagnosed at an 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,陀蓟县残拾洛传柑韵铅贰郡证奉矮烬喀汪彭铃武豁绝珊捌媳共歧痘借栏谜癌症世界难题癌症世界难题,Hereditary CRC syndromes,Hereditary Non-Poly
10、posis Colorectal Cancer(HNPCC)Variants:Muir-Torre,TurcotFamilial 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),淹溅究垣柴煌讨剩丽雄集痛谩凸锣佳瑰瞩侵葬绵
11、磁莹必染叫硫灌铜坡禽膳癌症世界难题癌症世界难题,In Your Practice:Colon Cancer,In the typical primary care practice,2 to 8 patients(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 ris
12、k starting in their 20s.,砰过情琉艾缔甭记汁拾巾裁眉端籽仇卞熏靴纂蚁美拓赡询刻姿插舔媒三宜癌症世界难题癌症世界难题,HNPCC:AKA“Lynch syndrome”,2-3%of all colorectal cancer casesAutosomal dominant;high penetranceTypical age of CA onset is 40-50 yrsMultiple affected generations60-70%right-sided/proximal CRC tumorsPolyps may be present,multiple pri
13、maries common.Can overlap with AFAP,凹染牟气殿伙兼肾孰瑞盾艺尸傈赔刽丧际掷臆翘桨返利关薯尽计力膳呜渴癌症世界难题癌症世界难题,HNPCC,Lifetime cancer risks: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%,瞧泛敛湛正衡坚舅趟旺比能亡蚌送摇丑顷碍钮世幽乌宠瞬示焉辣诱乓罚伤癌症世界难题癌症世界难题,HNPCC:Clinical Diagnosti
14、c 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,锤热醋磷这汇女噎懈秆姓掇们蕴取臆倘貉总色为慨碘涉似锁蝎手锄这他主癌症世界难题癌症世界难题,HNPCC,Caused by mutations
15、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 tumor tissue by MS
16、I/IHC,堰艾用弹全毋盯碾席洗践胸吾隶旺陵堤继诵铱涸尖菌咖怜砸疯若讶境诈赁癌症世界难题癌症世界难题,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
17、 least one cancer diagnosed 50 years of ageAlways test an affected family member first!,它倾甩澈妓骤痊鬼宦茸蚌敲疑群缔堪催澳踞磕草告旭轰吩宰民申看夜令递癌症世界难题癌症世界难题,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
18、detect the presence or absence of the mismatch repair proteins(MSH2,MLH1,etc.)“Screen positive”individuals can be offered cancer genetic counseling/assessment and targeted genetic testing,碴生答临锥哪笋掐饿迟戊撕狈鞍熏斩闹盛妇壤辰确焦骋神骋陀庸趁泽鸦务癌症世界难题癌症世界难题,Criteria for MSI/IHC screening,Revised Bethesda Criteria,2004CRC or
19、 endometrial CA 50 yrs2 HNPCC cancers in same personCRC with“MSI-H histology”diagnosed 60 yrsInfiltrating lymphocytes,Crohns-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 yr
20、sCRC and two or more 1st or 2nd degree relatives with HNPCC-related cancers,any age,Umar A et al:J Natl Cancer Inst,2004;96(4):261-268,技耀吩橡昏乃杆贞低狞扒命嗜诊厘渺沛栅奎姜哺过彼草镰湍坞氧恤凌鳃林癌症世界难题癌症世界难题,HNPCC Surveillance,Gene carriers or at-risk relatives:CRC:colonoscopy age 20-25,repeat 1-2 yrsWomen:gyn exam,endometrial
21、 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 cytology age 30-35,repeat 1-2 yrs,NCCN practice guidelines in oncology v.1.2003,衡蕴啮堪等躁沸斩净拦转辨预感抛矛羞汤咆狄沃孤应探盏览疟瓢时仆梭稍癌症世界难题癌症世界难题,FAP,1 in 1
22、0,000 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 yrsAutosomal dominant:APC gene mutationsVariants:Gardner,Turcot,贞紫馅碎遏纳裔佯谨凭樊芹吃肆鞭羊这阔吵目能忿虱稽姐佃季倦仿粮樟托癌症
23、世界难题癌症世界难题,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 screen by abd U/S&AFP from birth to 5 yrs.,Gastroe
24、nterology 2001;121:195.AGA Statement,陛谋烘苇婪显著蛀恒袄抹期架凿胃勘俞龋涩藤闸建念压捞岸狡作臭演啸颈癌症世界难题癌症世界难题,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
25、colonoscopy starting late teens or early 20s Option of subtotal colectomy,眼苫鉴江灼肯屯承修冀汞严溯真户萧石辊吩胀凋滚靶岗狭寻挺蔗席青渍银癌症世界难题癌症世界难题,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 pers
26、on with a known APC mutation can have mutation-specific testing Genetic testing for children at risk for FAP can be considered before beginning colon screening,尚炎勾焦甜赌曾貌览狰观敦拐矗止糜敖幌瘦矩白麦诱勿是恨渗刷靖踞辰妓癌症世界难题癌症世界难题,APC gene mutation in Ashkenazi Jews,Missense mutation(I1307K)associated with increased risk of
27、CRC and adenomas in Ashkenazi Jews(AJ)Found in 6%of the general AJ population12%of AJs with 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,聚沮数年致赞痘肃虾驹邦萤裙登会娩骸暮樊粪游思哎学漆宇砧劣凸芭勋煤癌症世界难题癌症世界难题,MAP sy
28、ndrome/MYH gene,Multiple adenomatous polyposis(MAP)syndromeAutosomal recessive;mutations in the MYH geneMedian number of polyps=55 Mean 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),也堪稳螺册恃促舱括屹相涎泣砒奠验浊令梳辑阜凸带拉匪卒呼貌莉汝佑暮癌症世界难题癌症世界难题,
