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  • ~75% of cases of CRC are sporadic only 7% of sporadic cases occur <55 ~15-20% are “familial” / multifactorial – genetic testing not generally available for low penetrance genes associated with increased risk of CRC ~5-8% are hereditary (defined cancer susceptibility syndromes caused by single genes)
  • Typical age of onset is 40-50, range from 14-82 yrs Preponderance of right-sided/proximal tumors – 60% Polyps may be present (usually few to < 100), multiple primaries common. Can overlap AFAP so consider this diagnosis if >20 colon polyps detected.
  • Cancer Risk with HNPCC: CRC - 80% lifetime, 40% for 2nd primary
  • Autosomal dominant condition caused by mutations in one of a number of mismatch repair genes MSH2, MLH1, MSH6, PMS1, or PMS2, others(?) Sequencing of the MSH2 and MLH1 genes can identify up to 60-70% of HNPCC Microsatellite Instability (MSI) and Immunohistochemistry (IHC) testing on tumor tissue can be used to screen for possible HNPCC Genetic testing should be done on an affected family member, only after genetic counseling and informed decision-making
  • Option of subtotal colectomy if polyps too numerous – AFAP does not generally affect the rectum, although continued surveillance is recommended.
  • APC gene analysis (either by protein truncation testing [PTT] or sequencing) can confirm a suspected diagnosis PTT detects 80-90% of affected persons (FAP) Gene sequencing detects up to 95% of affecteds Family members of a person with a known APC mutation can be tested for carrier status Testing at-risk children – can be considered before beginning screening (10-12yrs) Detection rate for AFAP is not known
  • Type of primary cancer(s) in each affected relative Age of disease onset in each affected relative earlier onset generally confers higher risk for close relatives Cancer status in 1 st and 2 nd degree relatives (often discounted) Cancer status in both sides of the family (paternal family history often overlooked when assessing risk of “female” cancers)
  • Any patient with 2 or more family members (same side) with early onset CRC (<50 yrs) Any colon cancer case before 40 yrs Woman with endometrial cancer <45 and family history of early onset CRC Persons with more than one primary CRC <50 yrs or with both endometrial and CRC Autosomal dominant pattern of cancers in the same lineage Insurance coverage: Some insurers and some plans will cover cancer genetic risk assessment/cancer genetic counseling. Others will not. More difficult to obtain coverage for unaffected person with a family history than an affected person. Pre-authorization recommended. Pre-authorization for cancer genetic testing is important as tests are expensive. The genetic counselor will facilitate the pre-auth for testing if indicated and if patient decides to have testing. Insurance discrimination – needs to be discussed before insurer is contacted regarding coverage.
  • About 10% of all people have a 1 st degree relative with CRC, which increases risk 2-fold Risk for CRC increases with: degree of relationship and # of affected members younger age of onset presence of extracolonic tumors, multiple primaries
  • ACBE = air contrast barium enema. FOBT = fecal occult blood test
  • Psychological implications of test results (benefits and risks) Risks of insurance/employment discrimination – current data 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 (how and to whom?)
  • Genetic consultations are available by phone with OHSU medical geneticists. See Oregon Genetics provider list for the phone number.
  • Again, it is important for patient to check own insurance policy to see if genetics referral is covered. Some patients will not want their insurance notified of a genetics referral because of concerns about insurance discrimination.
  • Transcript

    • 1. Genetics and Primary Care Familial Cancer Risk Assessment Colorectal Cancer
    • 2. 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 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. C haracteristics 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 f amily 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)
        • 3 or more relatives with an HNPCC-related cancer, one of whom is a 1 st degree relative of the other two
        • 2 or 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 Testing A fter 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 1 st 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 1 st degree relative with an HNPCC-related cancer, one diagnosed <50 yrs
      • CRC and two or more 1 st or 2 nd 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 1 st 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 1 st or 2 nd decade
        • 50% lifetime risk of CRC; AOO in 30’s
        • Increased risk gastric, GI, pancreatic CA
      • ~50% of cases have mutations in either the MADH4 or BMPR1A genes
    • 27.  
    • 28. What can YOU do?
    • 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. 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
    • 31. 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
    • 32. Family History Details to Record
      • Type of primary cancer(s) in each relative
      • Age of disease onset in each relative
      • Cancer status in 1 st and 2 nd degree relatives
      • Cancer status in both sides of the family
      • Other medical findings
    • 33.  
    • 34. 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
    • 35. 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 1 st degree relative with an HNPCC-related cancer, one diagnosed <50 yrs.
      • * Same side of family
    • 36. 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
    • 37. 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
    • 38. 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
    • 39. Family History: Empiric Risks
      • Lifetime Risk CRC
      • General population in US ~2 to 6%
      • One 1 st degree relative w/CRC 2-3 fold
      • Two 1 st degree relatives w/CRC 3-4 fold
      • 1 st degree relative w/CRC <50 3-4 fold
      • One 2 nd or 3 rd degree relative w/CRC ~1.5-fold
      • Two 2 nd degree relatives w/CRC 2-3 fold
    • 40. Goal: Classification Family Hx Assessment Personalized prevention recommendations Referral for genetic evaluation with personalized prevention recommendations Standard prevention recommendations Intervention Average Moderate (“Familial”) High/Genetic Risk Classification
    • 41. CRC Risk Management
      • Age to Begin Average Risk 50 yrs
      • No family history CRC OR
      • One 2 nd or 3 rd degree relative with CRC
      • - FOBT annually + Flex sig every 5 yrs; OR
      • - Colonoscopy every 10 yrs; OR
      • - DCBE every 5 yrs
    • 42. CRC Risk Management
      • Moderate/Family history Age to begin
      • 1. Two 1 st degree relatives with CRC any age 40 years*
      • or one 1 st degree relative with CRC < 60
      • - Colonoscopy every 5 yrs
      • 2. One 1 st degree relative with CRC >60 or 40 years
      • two 2 nd degree relatives with CRC any age
      • - Average risk screening
      • * Or 5-10 yrs earlier than earliest case in family
      Gastroenterology: 2003;124:544-560
    • 43. 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
    • 44.  
    • 45. 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
    • 46. 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
    • 47. 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
    • 48. 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 polyps removed
        • No other significant history
        • Both sides of the family are Northern European Caucasian
    • 49. Pedigree: Case 1 Key: Endometrial CA Colorectal CA Adenomatous polyps Dx 38 Dx 50 88 yr 63 yr 4 polyps 50 yrs. CRC Dx 48 61 yr 38 yr 10 yr 8 yr 35 yr French, Irish, Scottish German, English
    • 50. 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
    • 51. 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
    • 52. Case 2: Pedigree 30 yrs 34 yrs Key: CRC Breast CA Cervical CA BrCa 85 yrs d.87 Colon Ca 54 yrs Cerv.Ca 30 yr 55 58 Cerv.Ca 32 yr 60 d. 58 MI 84 56 CRC 79 d.82 Italian Irish German
    • 53. Case 2: Ted
      • Verify Diagnoses! Obtain and review pathology reports on all reported cancers, whenever possible
      • If diagnoses are correct: Ted has no family history indicative of a known colon cancer syndrome (HNPCC, FAP, other)
        • Ted’s lifetime risk of colorectal CA is increased 2 to 3 fold due to one affected first degree relative (>50)
        • Moderate/familial risk: Screening by colonoscopy starting at age 40, or 10 yrs earlier than earliest case in family, is reasonable
    • 54. Oregon Genetics Providers
      • Portland
        • Oregon Health & Science University
        • Legacy Health Care
        • Northwest Perinatal Services
        • Kaiser-Permanente
      • Eugene
        • Center for Genetics & Maternal Fetal Medicine
      • Bend
        • Genetic Counseling of Central Oregon (cancer only)
    • 55. Referral for Genetic Services
      • Consult “Genetic Services Contact List”
      • Phone consultations available:
        • OHSU Genetics Consult Line: 503-494-5516
      • Refer patients by phone, fax, mail, or patient self-referral
      • ‘ Indications for Referral’ in resource packet
        • Preconception/Prenatal
        • Pediatric
        • Adolescent/Adult
    • 56. Resource Materials
      • Patient pamphlets:
        • ‘ Do You Have Cancer in Your Family?’
        • ‘ Genetic Testing: A Fact Sheet’
      • Web-based cancer genetics resource list
      • Hereditary Colon Cancer Association
        • www.hereditarycc.org
      • Resource materials at www.oregongenetics.org
      • Genetics tutorials on www.modimes.org