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1、Genetics and Primary Care,Familial Cancer Risk Assessment Colorectal 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 aden
2、omatous 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:/,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 r
3、eveals: 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 & 34 Maternal grandmother: breast cancer age 85,Outline,Hereditary colorectal cancer syndromes Cancer family
4、history a primary tool Evaluating your patients for familial CRC risk Genetic counseling and testing for hereditary colorectal cancer How, when, where to refer patients for genetic services,Colorectal Cancer,5-8% of all cases of CRC are hereditary 15-20% are “familial” / multifactorial 75% of cases
5、are sporadic Feuer EJ: DEVCAN: National CA Inst. 1999,Characteristics of Average Risk,No well-defined threshold between sporadic and familial CRC at this time Probably safe to include individuals with: No personal risk factors or family history of CRC One 2nd or 3rd degree relative with CRC 60 years
6、 with no other family history of CRC,Characteristics of “Familial” CRC,“Clustering” of colon cancer cases in the family ( 50 at diagnosis) without clear dominant pattern, or One close relative with CRC 60 yrs and family history does not meet criteria for known hereditary CRC syndromes Likely to be m
7、ultiple low pentrant genes plus environmental factors at play Family members warrant earlier CRC screening Starting 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 rel
8、atives with colorectal cancer One or more diagnosed at an early age (50) Sequential generations affected Except in autosomal recessive syndromes Other cancers in the family known to be associated with CRC (uterine, ovarian, GI) Multiple primary tumors or polyps,Hereditary CRC syndromes,Hereditary No
9、n-Polyposis Colorectal Cancer (HNPCC) Variants: Muir-Torre, Turcot Familial Adenomatous Polyposis (FAP) Variants: Gardner, Turcot Attenuated FAP APC mutation in Ashkenazi Jews Others: Multiple adenomatous polyposis syndrome/MYH gene (MAP) Peutz-Jeghers syndrome (PJS) Familial Juvenile Polyposis (FJP
10、),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 risk starting in
11、 their 20s.,HNPCC: AKA “Lynch syndrome”,2-3% of all colorectal cancer cases Autosomal dominant; high penetrance Typical age of CA onset is 40-50 yrs Multiple affected generations 60-70% right-sided/proximal CRC tumors Polyps may be present, multiple primaries common. Can overlap with AFAP,HNPCC,Life
12、time 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%,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 rel
13、ative of the other two 2 or more successive generations affected 1 or more cancers diagnosed before age 50,HNPCC,Caused by mutations or deletions in mismatch repair (MMR) genes MSH2, MLH1, MSH6, (PMS2) 90% of detectable mutations in MSH2 and MLH1 50% of families meeting Amsterdam II Criteria have de
14、tectable mutations Testing/screening options: Direct genetic testing of MMR genes (in select families) Initial screening of the tumor tissue by MSI/IHC,Proceed Directly To Genetic Testing After genetic counseling and informed consent!,IF: Family history fulfills Amsterdam II criteria or Patient has
15、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 Always test an affected family member first!,MSI/IHC screening,Microsatellite Instability (MSI) on tumor tissue can be used to screen for HNPCC in sele
16、ct cases Immunohistochemistry (IHC) on tumor tissue can be used to 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,Criteria for MSI/IHC screening,Revised B
17、ethesda 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 HN
18、PCC-related cancer, one diagnosed 50 yrs CRC 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,HNPCC Surveillance,Gene carriers or at-risk relatives: CRC: colonoscopy age 20-25, repeat 1-2 yrs Women: gyn exam, endome
19、trial aspiration, TV U/S, CA-125 (?) age 25-35, repeat 1-2 yrs If one HNPCC family member affected w/the following: Stomach CA: EGD age 3-35, repeat 1-2 yrs Urinary tract CA: urine cytology age 30-35, repeat 1-2 yrs,NCCN practice guidelines in oncology v.1.2003,FAP,1 in 10,000 incidence 100s to 1000
20、s of colonic adenomas by teens Cancer risk: colon, gastric, duodenum (periampulla), small bowel, pancreas, papillary thyroid, childhood hepatoblastoma 7% risk of CRC by 21 yrs; 93% by 50 yrs Autosomal dominant: APC gene mutations Variants: Gardner, Turcot,FAP surveillance,Colon Annual sigmoidoscopy,
21、 age 10-12 yrs Prophylactic colectomy following polyp detection w/continued surveillance of rectum, ileal pouch Duodenal/gastric EGD age 25, repeat 1-3 yrs Thyroid Annual PE, age 10 Hepatoblastoma Annual screen by abd U/S & AFP from birth to 5 yrs.,Gastroenterology 2001; 121: 195. AGA Statement,Atte
22、nuated FAP,20 to 100 polyps, usually more proximal Onset later than FAP, average AOO = 50 Lifetime risk of CRC = 80% Extracolonic tumors occur at same rate as FAP Variant of FAP, mutations in same APC gene Surveillance: annual colonoscopy starting late teens or early 20s Option of subtotal colectomy
23、,Genetic Testing: FAP/AFAP,Test an affected family member first! After genetic counseling and informed consent APC gene testing can confirm a suspected diagnosis Family members of a person with a known APC mutation can have mutation-specific testing Genetic testing for children at risk for FAP can b
24、e 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 population 12% of AJs with CRC 29% of AJs with CRC and a positive family history Lifeti
25、me 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) syndrome Autosomal recessive; mutations in the MYH gene Median number of polyps = 55 Mean age of polyp diagnosis = 30-50 years Polyps mainly small, mildly dysplastic tubular adenomas. Some tubulovillous, hyperplastic, serrated adenomas, microadenomas 30% of individuals with 15-100 polyps have homozygous mutations in the MYH gene Genetic testing should be offered if 15 polyps (and APC gene testing negative),