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Genetics and Primary Care

Genetics and Primary Care

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Genetics and Primary Care

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  1. Genetics and Primary Care Familial Cancer Risk Assessment Colorectal Cancer

  2. Case1: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 polyps removed • No other significant history • Both sides of the family are Northern European Caucasian

  3. 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 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

  4. Outline • Hereditary colorectal cancer syndromes • Cancer family 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

  5. Colorectal Cancer • ~5-8% of all cases of CRC are hereditary • ~15-20% are “familial” / multifactorial • ~75% of cases are sporadic Feuer EJ: DEVCAN: National CA Inst. 1999

  6. 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 with no other family history of CRC

  7. 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 multiple 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

  8. Characteristics of Hereditary CRC • Multiple relatives 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

  9. Hereditary CRC syndromes • Hereditary Non-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 their 20’s.

  11. 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

  12. 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%

  13. HNPCC: Clinical Diagnostic Criteria • Amsterdam II Criteria (3-2-1 rule) • 3or more relatives with an HNPCC-related cancer, one of whom is a 1st degree relative of the other two • 2or more successive generations affected • 1 or more cancers diagnosed before age 50

  14. 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 detectable mutations • Testing/screening options: • Direct genetic testing of MMR genes (in select families) • Initial screening of the tumor tissue by MSI/IHC

  15. Proceed Directly To Genetic TestingAfter 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 • Always test an affected family member first!

  16. MSI/IHC screening • Microsatellite Instability (MSI) on tumor tissue • can be used to screen for HNPCC in select 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

  17. Criteria for MSI/IHC screening Revised 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 <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

  18. HNPCC Surveillance • Gene carriers or at-risk relatives: • CRC: colonoscopy age 20-25, repeat 1-2 yrs • Women: gyn exam, endometrial 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

  19. FAP • 1 in 10,000 incidence • 100’s to 1000’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

  20. FAP – surveillance • Colon • Annual sigmoidoscopy, 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

  21. Attenuated 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 20’s • Option of subtotal colectomy

  22. 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 be considered before beginning colon screening

  23. 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 • Lifetime risk of CRC in mutation carrier is 10-20% • Screening: colonscopy every 2-5 yrs starting at 35 yrs

  24. 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)

  25. Peutz-Jeghers syndrome • <1% of all CRC cases • Hamartomatous polyps of GI tract as early as 1st decade • Mucocutaneous hyperpigmentation • lips, mouth, buccal mucosa, fingers • Usually seen in children < 5 yrs • Cancer risk: • colon, small intestine, stomach, pancreas, breast, ovaries, uterus, testes, lungs, kidneys • Mutations in STK11 gene • found in 70% of familial cases and 30-70% of sporadic cases

  26. Familial Juvenile Polyposis • <1% of all CRC cases • Autosomal dominant • 5 or more juvenile polyps in colon or GI tract • Appear in 1st or 2nd decade • 50% lifetime risk of CRC; AOO in 30’s • Increased risk gastric, GI, pancreatic CA • ~50% of cases have mutations in eitherthe MADH4 or BMPR1A genes

  27. What can YOU do?

  28. CRC Risk Screening: Steps to take • Take a thorough cancer family history • Does family history meet hereditary criteria? • If yes, refer to genetics • Classify based on family history: average, moderate or high risk. • Create surveillance plan based on risk level

  29. CRC Risk Screening: Steps to take • Take a thorough cancer family history • Does family history meet hereditary criteria? • If yes, refer to genetics • Classify based on family history: average, moderate or high risk. • Create surveillance plan based on risk level

  30. Family Health History “The family tree has become the most important genetic test of all. The more you know, the more tools you have to practice preventive medicine” Donna Russo, Certified Genetic Counselor, NY Presbyterian-Columbia Hospital

  31. Family History Details to Record • Type of primary cancer(s) in each relative • Age of disease onset in each relative • Cancer status in 1stand 2nd degree relatives • Cancer status in both sides of the family • Other medical findings

  32. CRC Risk Screening: Steps to take • Take a thorough cancer family history • Does family history meet ‘potentially hereditary’ criteria? • If yes, refer to genetics • Classify based on family history: average, moderate or high risk. • Create surveillance plan based on risk level

  33. Consider Genetics Referral for: • Two or more family members with CRC* at least one <50 • Three or more family members w/CRC*; any age • Patient with colon cancer before 40 yrs • Endometrial cancer and family history of CRC <50 • Persons with more than one primary CRC <50 yrs or with both endometrial CA and CRC • Family or personal history of CRC and one or more 1st degree relative with an HNPCC-related cancer, one diagnosed <50 yrs. *Same side of family

  34. Consider Genetics Referral for: • MSI and/or IHC tumor results suspicious for HNPCC • Autosomal dominant pattern of cancers in the family • Persons with 15 or more adenomatous colorectal polyps • Persons with multiple hamartomatous or juvenile GI polyps • Persons with a family history of a known hereditary cancer syndrome

  35. CRC Risk Screening: Steps to take • Take a thorough cancer family history • Does family history meet hereditary criteria? • If yes, refer to genetics • Classify based on family history: average, moderate or high risk. • Create surveillance plan based on risk level

  36. Empiric Risk of CRC • Risk for CRC based on family history increases with: • Closer degree of relationship and # of affected members • Younger age of onset • Presence of extracolonic tumors, multiple primaries

  37. Family History: Empiric Risks Lifetime Risk CRC General population in US ~2 to 6% One 1st degree relative w/CRC 2-3 fold Two 1st degree relatives w/CRC 3-4 fold 1st degree relative w/CRC <50 3-4 fold One 2nd or 3rd degree relative w/CRC ~1.5-fold Two 2nd degree relatives w/CRC 2-3 fold

  38. Goal: Classification Assessment Risk Classification Intervention Standard prevention recommendations Average Moderate (“Familial”) Personalized prevention recommendations Family Hx Referral for genetic evaluation with personalized prevention recommendations High/Genetic

  39. CRC Risk Management Age to BeginAverage Risk50 yrs • No family history CRC OR • One 2nd or 3rd degree relative with CRC - FOBT annually + Flex sig every 5 yrs; OR - Colonoscopy every 10 yrs; OR - DCBE every 5 yrs

  40. CRCRisk Management Moderate/Family historyAge to begin 1. Two 1st degree relatives with CRC any age 40 years* or one 1st degree relative with CRC < 60 - Colonoscopy every 5 yrs 2. One 1st degree relative with CRC >60 or 40 years two 2nd degree relatives with CRC any age - Average risk screening * Or 5-10 yrs earlier than earliest case in family Gastroenterology: 2003;124:544-560

  41. CRC Risk Management Age to Begin HNPCC or suspected HNPCC 20-25 yrs 1. Colonoscopy every 1-2 yrs 2. Genetic counseling; consider genetic testing FAP or suspected FAP 10-12 yrs 1. Flex sig or colonoscopy every1-2 yrs 2. Genetic counseling; consider genetic testing

  42. Cancer Genetic Counseling • Full pedigree analysis and risk assessment • Discussion of: • Personal cancer risks based on family history • Genetic testing options and risk of mutation • Advantages, risks and limitations of genetic testing • Personalized, risk-based screening and prevention options • Support resources

  43. Cancer Genetic Testing:Elements of Informed Consent • Information on specific test(s) being considered • Implications of positive, negative, uninformative results • Options for risk assessment and management without genetic testing • Risk of passing a mutation to offspring • Technical accuracy of test • Fees involved in testing and counseling • Option of DNA banking

  44. Cancer Genetic Testing: Informed Consent (cont.) • Psychological implications of test results • Risks of insurance/employment discrimination • Confidentiality issues • Options for and limitations of medical surveillance and strategies for prevention following testing • Importance of and guidance on sharing results with at-risk relatives • Results disclosure American Society of Clinical Oncology, March, 2003

  45. Case1: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 polyps removed • No other significant history • Both sides of the family are Northern European Caucasian

  46. Pedigree: Case 1 French, Irish, Scottish German, English 88 yr Dx 50 61 yr 63 yr CRC Dx 48 4 polyps 50 yrs. Key: 38 yr 35 yr Endometrial CA Dx 38 Colorectal CA Adenomatous polyps 8 yr 10 yr

  47. Case 1: Assessment • Joan meets Amsterdam II Criteria and is at risk for HNPCC • Refer to genetics for cancer genetic counseling and discussion of genetic testing for HNPCC • Testing options: • Direct gene testing of MLH1 and MSH2 OR • MSI/IHC screening of tumor tissue with gene sequencing if MSI positive