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Prepared by: June C Carroll MD, CCFP, FCFP Sydney G. Frankfort Chair in Family Medicine Mount Sinai Hospital , University of Toronto Andrea Rideout MS, CGC, CCGC Certified Genetic Counsellor Project Manager – The Genetics Education Project Sean Blaine BSc, MD, CCFP

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Hereditary Colorectal Cancer


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    1. Prepared by:June C Carroll MD, CCFP, FCFP Sydney G. Frankfort Chair in Family Medicine Mount Sinai Hospital, University of Toronto Andrea Rideout MS, CGC, CCGC Certified Genetic Counsellor Project Manager – The Genetics Education Project Sean Blaine BSc, MD, CCFP Mount Sinai Hospital, University of Toronto Stratford, Ontario Funded by: Ontario Women’s Health Council Version: January 2010 Hereditary Colorectal Cancer

    2. Acknowledgments • Reviewers: Members of The Genetics Education Project (see slide 51) + Kara M. Semotiuk, MS, (C)CGC Genetic Counsellor Heidi Rothenmund, MS, (C)CGC Genetic Counsellor Familial GI Cancer Registry, Mount Sinai Hospital • Funded by: Ontario Women’s Health Council as part of its funding to The Genetics Education Project * Health care providers must use their own clinical judgment in addition to the information presented herein. The authors assume no responsibility or liability resulting from the use of information in this presentation.

    3. Outline • Sporadic verses familial cancer • Hereditary colorectal cancer syndromes • Referral guidelines • Benefits, risks and limitations of genetic testing • Management • Case examples

    4. Cancer All cancer involves changes in genes…. Threshold effect: • During mitosis & DNA replication • mutations occur in the cell’s genetic code • Mutations are normally corrected by DNA repair mechanisms • If repair mechanism or cell cycle regulation is damaged • Cell accumulates too many mutations • reaches ‘threshold’ • tumour development

    5. Sporadic Cancer • All cancer arises from changes in genes…. • But NOT all cancer is inherited • Most CRC is sporadic~75 – 80% • Due to acquired mutations throughout a person’s lifetime: • Causes unknown – multifactorial • Interaction of many factors: age, environment, lifestyle, chance, unknown factors • Sporadic cancer generally has a later onset

    6. Clustering of Cancer in Families • ~6% lifetime risk of CRC in general population • ~20% of people with CRC have a family history: • ~15% of CRC is familial: • Environmental factors • Chance • Undiscovered gene mutation • Generally not eligible for genetic testing • ~5% of CRC cancer is hereditary • Caused by an inherited gene mutation that puts them at increased risk for cancer • Majority is Lynch syndrome/HNPCC (Hereditary Non-Polyposis Colorectal Cancer) • Small fraction is Familial Adenomatous Polyposis (FAP) or other rare cancer syndromes • May be eligible for genetic testing

    7. Proportion of Hereditary CRC Familial ~15% Hereditary ~5% Lynch syndrome ~ 2-5% FAP ~ <1% Sporadic 80%

    8. Knudson ‘two-hit’ Model Sporadic Cancer ONE HIT (hit=mutation) Birth: Two non-mutated copies of the gene SECOND HIT One mutation in one gene; Second gene non-mutated Two mutations - one in each gene CANCER

    9. Knudson ‘two-hit’ Model Hereditary Cancer ONE HIT (hit=mutation) SECOND HIT Birth: One mutation in one gene; Second gene non-mutated Two mutations - one in each gene CANCER

    10. Compared to sporadic cancer people with hereditary cancer have… • A higher risk of developing cancer • A younger age of onset of cancer • Generally < 50 years of age • Multiple primary cancers • Generally have a family history of cancer Hereditary cancer is less common in the general population than sporadic cancer

    11. Inherited Colorectal Cancer Two common syndromes: • Lynch syndrome • Also known as Hereditary Non Polyposis Colorectal Cancer or HNPCC • ~2 - 5% of colorectal cancer • Prevalence of 1 in 200 - 2,000* • Familial Adenomatous Polyposis (FAP) • <1% of colorectal cancer • Prevalence of 1 in 8,000 – 14,000* • Autosomal dominant inheritance *Prevalence depends on population

    12. Autosomal Dominant Inheritance • Legend • B:CRC gene with mutation • b: normal CRC gene Unaffected CRC mutation bb Bb bb Bb Bb bb Susceptible CRC gene Population Risk Population Risk Susceptible CRCgene

    13. Colorectal cancer genes… when mutated • Lynch syndrome (HNPCC): • Mutations in DNA repair genes lead to an accumulation of mutations which may result in malignancy. • FAP: • Mutations in a tumour suppressor gene cause an increase in cell proliferation and a decrease in cell death.

    14. Lynch syndrome (HNPCC) • Lynch syndrome is genetically heterogeneous • Clinical testing available for 4 genes: MLH1 & MSH2 (most common), MSH6 & PMS2 • Research testing may be available for other genes • High penetrance • Characterized by: • Earlier onset than sporadic cancer • More aggressive, proximal, right sided tumours • Risk for extra-colonic tumours • Distinct tumour pathology

    15. Cancer Risk in Individuals with Lynch syndrome (HNPCC) to Age 70 Compared to General Population from: http://www.genetests.org

    16. Familial Adenomatous Polyposis • Chromosome 5, APC gene • High penetrance • Characterized by: • Early onset • >100 adenomatous polyps • Variant form: • Attenuated FAP may occur with >10 but <100 polyps.

    17. Consequences of FAP • Colorectal adenomatous polyps begin to appear at an average age of 16 years (range 7-36 years) • Average age at diagnosis: 34-43 years, when >95% have polyps From: http://www.genetests.org

    18. Consequences of FAP • ~50-90% develop small bowel polyps • lifetime risk of small bowel malignancy is 4-12% • ~50% develop gastric polyps • ~10% gastric cancer • ~10% develop desmoid tumours

    19. Red Flags for hereditary colorectal cancer – consider referral to genetics • Multiple cases in family with Lynch syndrome/HNPCC spectrum of cancers with at least 1 relative with CRC or endometrial CA • CRC at <45 years • Multiple Lynch syndrome cancers in 1 family member • Family member with FAP or >10 adenomatous polyps • Family member with known mutation • Family member with colonic adenoma or cancer with high microsatellite instability (MSI) • See extra slides following references for more information about MSI • Not all who are referred will have genetictesting

    20. Risk of Developing Colorectal Cancer From: http://www.cancer.gov

    21. Case • Jane - healthy 26 y.o. • Office visit for a routine pap smear and renewal of birth control pills • History: • Any cancer in the family? • Mother with breast cancer at 66

    22. Case continued… • Father’s side of the family: • uncle - CA ureter age 72 • uncle - CA colon age 56 • aunt - double primary: endometrial CA age 45, colon CA age 68 • 1 cousin - endometrial CA age 40 • 2 cousins - both have colon CA

    23. Jane’s Family Pedigree LEGEND Kidney Colon Endometrial Breast Accident Stroke Nat Causes A&W Mary Dx 45 CA Endometrial Dx 68 CA Colon Steve Dx 72 CA Kidney Bob Dx 56 CA colon Paula Dx 66 CA- Br MI 72 Kevin, 67 A&W A&W A&W A&W Jeana Dx 40 Ca-Endometrial Christa Dx 52 CA – Colon Linda Dx 38 CA - colon A&W A&W Jane, 26

    24. Jane was referred to genetics… A genetics consultation involves: • Detailed family history information • Pedigree documentation • Confirmation of cancer history: pathology reports/death certificates • Medical & exposure history • Empiric risk assessment • Hereditary cancer / genetic risk assessment • Psychological assessment

    25. …A genetics consultation involves: • Assessment of eligibility for genetic testing • Availability of living affected relative to be tested first • Discussion of risks, benefits & limitations of test • Testing and disclosure of genetic test results • May be months before results are available • Determining patient’s thoughts about colorectal cancer - motivations for testing • Screening/management recommendations

    26. Recommendations for Jane’s family • Jane’s paternal family history is suggestive of Lynch syndrome/HNPCC. • Jane was asked to discuss genetic testing with her family members diagnosed with cancer. • Appropriate to test an affected member first. • If a mutation found in one of the Lynch syndrome genes then sequential testing of the family can be performed. • If Jane’s family declines genetic testing then family members should follow high risk screening recommendations for CRC. • Colonoscopy q1-2 years; consider referral to a GYN to discuss endometrial cancer screening

    27. Results from Genetic Testing • Positive • Deleterious mutation identified • Negative • Interpretation differs if a mutation has previously been identified in the family • Mutation known – true negative • Mutation unknown – uninformative • Variant of unknown significance • Significance will depend on how variant tracks through family, i.e. is variant present in people with disease? • Can use software to predict functional significance • Check with lab: ? reported previously

    28. Potential Benefits: Clinical intervention may improve outcome Family members at risk can be identified Positive health behaviour can be reinforced Reduction of uncertainty Potential Risks: Adverse psychological reaction Family issues/distress Uncertainty -incomplete penetrance Insurance/job discrimination Confidentiality issues Intervention may carry risk Risks/Benefits/Limitations of genetic testingPositive test result

    29. Potential Benefits: Avoidance of unnecessary clinical interventions Emotional - relief Children can be reassured Potential Risks: Adverse psychological reaction (i.e. survivor guilt) Dysfunctional family dynamics Complacent attitude to health Risks/Benefits/Limitations of genetic testing? True Negative test result

    30. Potential Benefits: Future research may clarify test results Importance of positive health behaviour can be reinforced Some relief Potential Risks: Continue clinical inventions which may carry risks Complacent attitude to health Uncertainty Continued anxiety Risks/Benefits/Limitations of genetic testing? Uninformative test result

    31. What is the benefit of genetic testing?Can anything be done to change risk /outcome? • Patients with Lynch syndrome/HNPCC: • Colonoscopy beginning age 20-25 or 10 years younger than youngest CRC or adenomatous polyp diagnosis, whichever comes first • Subsequent colonoscopy every 1-2 years • Category of evidence III, grade C Vasen et al. J Med Genet. 2007; 44:353-362.

    32. What is the benefit of genetic testing? Can anything be done to change risk /outcome? • Evidence for screening in Lynch syndrome/HNPCC: • Cohort study of CRC screening – 15 yr F/U • Subgroup of Lynch syndrome carriers • CRC in 8/44 with colonoscopy q3 years vs. 19/46 controls ( p=0.02) • RR of CRC = 0.44 (95% CI 0.2-0.9) • RR of death = 0.35 (95% CI 0.1-0.99) • 15 yr survival 92% vs. 74% Jarvinin et al Gastroenterology 2000

    33. What is the benefit of genetic testing?Can anything be done to change risk /outcome? • Lynch syndrome/HNPCC gynecological cancers: • Little evidence re GYN cancer screening • Educate re symptoms of endometrial & ovarian cancer • Beginning age 30-35 consider 1-2 years: • Gynecological examination • Trans-vaginal ultrasound +/- aspiration biopsy • Category of evidence III, grade C • CA125 • Consider prophylactic hysterectomy and bilateral salpingo-oophorectomy (BSO) • Grade C Vasen et al. J Med Genet. 2007; 44:353-362

    34. Lynch syndrome - Evidence for screening for endometrial cancer (EC): • Finnish HNPCC registry – chart review for 10 years • N=175 EC screening; N=83 no EC screening • Screening consisted of: GYN exam (100%), trans-vaginal U/S (94%), endometrial biopsy (74%) • Median screening interval 3 years/ Median age 52 years • Screening group: 14 cases of EC detected • 11 cases by screening alone • 2 cases by manifesting symptoms (interval cancers) • 1 case occult cancer found at the time of hysterectomy • 0 EC deaths • No screening group: • Number of EC cases not reported • 6 EC deaths • Survival curves: 100% screening group; 92% no screening • Differences b/w survival curves not significant (P=0.4) Renkonen-Sinisalo Int J Cancer 2006:120:821-824

    35. What is the benefit of genetic testing? Can anything be done to change risk /outcome? • Lynch syndrome – evidence for risk reducing surgery • Chart Review of HNPCC mutation positive women • Hysterectomy N = 61 • No cases of endometrial cancer • No hysterectomy N = 254 • 69 cases of endometrial cancer – 33% • P<0.001 • Bilateral salpingo-oophorectomy (BSO) N=47 • No cases of ovarian cancer • No BSO N=223 • 12 cases of ovarian cancer – 5.5% • P=0.09 • No peritoneal cancers in the study period Schmeler et al. NEJM 2006;354261-269.

    36. What is the benefit of genetic testing? Can anything be done to change risk /outcome? • Lynch syndrome/HNPCC screening for other cancers: • ONLY if there is a family history of the type of cancer listed below - controversial • Gastric cancer • Gastroduodenoscopy q1-2 years beginning age 30 – 35 years • Urinary tract cancer • Renal U/S + urine cytology q1-2 years beginning age 30 to 35 years • Other cancers • Screen as per family history of skin, small bowel, pancreaticobiliary cancers

    37. What is the benefit of genetic testing?Can anything be done to change risk/outcome? • Patients with FAP: • Sigmoidoscopy every 1-2 years beginning at age 10 to 12 • subsequent colonoscopy every 1-2 years • Colonoscopy once polyps are detected • Colectomy • Annual colonoscopy if colectomy is delayed more than 1 year after polyps emerge

    38. Management of Mutation Carriers Consider… Psychosocial support to assist with: Adjusting to new information most adjust within 3-6 months subset remain psychologically distressed Making decisions regarding management Addressing family issues, self concept, body image Dealing with future concerns Referral to support groups

    39. Management of Mutation Carriers Consider… Additional psychosocial support may be needed for high risk individuals such as those with: History of depression/anxiety Poor coping skills Inadequate social support / conflict in the family Multiple losses in the family Loss of parent at a young age Recent loss Multiple surgical procedures

    40. Resources • The National Cancer Institute: • http://www.cancer.gov/ • Gene Tests: http://www.genetests.org • Colon Cancer Alliance: • http://www.ccalliance.org/ • Canadian Cancer Society: www.cancer.ca • Cancer Genetics Support Group of Canada (CHGSGC): Contact Name: Nancy Schofield, President 16 Redford Road Canada London, ON N5X 3V5 Email: wschofield@odyssey.on.ca

    41. Case Examples

    42. Assessing the Risk for Hereditary CRC Using the Canadian Cancer Society triage card (below), what category of risk do the following family histories fit into?

    43. Legend Colon Case 1 Alz -75 Accident ‘Old Age’-82 Aneurysm-65 ↑Chol A&W Colon CA Dx 34 ID DM ↑Chol A&W A& W ↑Chol A&W Asthma Your Patient A&W

    44. Legend Colon Case 1

    45. Case 1 Answer: • Moderate risk for hereditary CRC • 1st or 2nd degree relative with CRC ≤35 • Management: • Offer referral to hereditary CRC/Genetics Clinic • Colonoscopy q 3-5 years starting 10 years younger than youngest CRC diagnosis • Educate patient about symptoms of endometrial cancer

    46. Legend Colon Endometrial Kidney Prostate Case 2 Prostate Ca Dx 72 Kidney Ca Dx 65 Alz -75 Aneurysm-65 A&W Colon Ca Dx 50 IDDM ID DM ↑Chol Colon Ca Dx 49 A&W A&W Endometrial Ca Dx 33 A&W Asthma Your Patient

    47. Legend Colon Endometrial Kidney Prostate Case 2

    48. Case 2 Answer: • High risk for hereditary CRC • ≥3 relatives on the same side of the family, at least 1 CRC and ≥2 with any combination of Lynch syndrome-associated cancer AND • 1 is a 1st degree relative of the other 2 and • 1 relative diagnosed <50 and • At least 2 successive generations (suggestive of Lynch syndrome) • Management: • Offer referral to hereditary CRC/genetics clinic • Colonoscopy q 1-2 years beginning age 20 or 10 years younger than youngest CRC diagnosis • Educate patient about symptoms of endometrial cancer

    49. Legend Colon Crohn’s disease Case 3 Accident Alz -75 Colon Ca Dx 74 Aneurysm-65 A&W ↑Chol IDDM ID DM ↑Chol A&W A& W A&W Asthma A&W Your Patient Crohn’s disease A&W

    50. Legend Colon Crohn’s disease Case 3