Hereditary Colorectal Cancer Prepared by: June C Carroll MD, CCFP, FCFP Sydney G. Frankfort Chair in Family Medicine Mount Sinai Hospital, University of Toronto Andrea L 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: March 2006
Acknowledgments • Reviewers: Members of The Genetics Education Project (see slide 51) + Kara M. Smith, 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.
Outline • Sporadic verses familial cancer • Hereditary colorectal cancer syndromes • Referral guidelines • Benefits, risks and limitations of genetic testing • Management • Case examples
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
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: • Cause unknown – multifactorial • interaction of many factors: age, environment, lifestyle, chance, unknown factors • Sporadic cancer generally has a later onset
Clustering of Cancer in Families • 7% 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 Hereditary Nonpolyposis Colorectal Cancer (HNPCC) • Small fraction is Familial Adenomatous Polyposis (FAP) or other rare cancer syndromes • May be eligible for genetic testing
Proportion of Hereditary CRC Hereditary 5% - HNPCC ~ 2-5% - FAP ~ <1% Familial 15% Sporadic80%
ONE HIT (hit =mutation) Knudson ‘two-hit’ Model Sporadic Cancer Birth: Two non-mutated copies of the gene SECOND HIT One mutation in one copy of the gene; One non-mutated copy Two mutations one in eachcopy of the gene CANCER
Knudson ‘two-hit’ Model Inherited cancer Born with one hit (hit = mutation) Birth: Two non-mutated copies of the gene SECOND HIT Birth: One mutation in one copy of the gene; One non-mutated copy Two mutations one in eachcopy of the gene CANCER
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 Hereditary cancer is less common in the general population than sporadic cancer
Inherited Colorectal Cancer Two common syndromes: • Hereditary Non-Polyposis Colon Cancer (HNPCC) • ~2 - 5% of colorectal cancer • Prevalence 1 in 200 - 2,000 • Familial Adenomatous Polyposis (FAP) • <1% of colorectal cancer • Incidence of 1 in 8,000 – 14,000 • Autosomal dominant inheritance
Autosomal Dominant Inheritance • Legend • B:CRC gene with mutation • b: normal CRC gene Unaffected Colon Cancer bb Bb bb Bb Bb bb Affected with Colon cancer Population Risk Population Risk Susceptible CRCgene
Colorectal cancer genes… when mutated • 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.
Hereditary Non-Polyposis Colon Cancer • HNPCC is genetically heterogeneous • 5 genes: • MLH1 & MSH2 (most common), MSH6, PMS1 & PMS2 • High penetrance • Characterized by: • Earlier onset than sporadic cancer • More aggressive, proximal, right sided tumours • Risk for extra-colonic tumours • Distinct tumour pathology
Cancer Risk in Individuals with HNPCC to Age 70 Compared to the General Population from: http://www.genetests.org
Familial Adenomatous Polyposis • Chromosome 5, APC gene • High penetrance • Characterized by: • Early onset • >100 adenomatous polyps • Variant form: • Attenuated FAP may occur with <100 polyps.
Consequences of FAP • Colorectal adenomatous polyps begin to appear at an average age of 15 years (range 7-36 years) • Average age at diagnosis: 32-39 years, when >95% have polyps From: http://www.genetests.org
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
Red Flags for hereditary colorectal cancer – consider referral to genetics • Multiple cases in family with HNPCC spectrum of cancers with at least 1 relative with CRC or endometrial CA • CRC at < 35 years • Multiple HNPCC cancers in one 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 • Not all who are referred will have genetic testing
Risk of Developing Colorectal Cancer From: http://www.nci.nih.gov
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
Case continued… • Father’s side of the family: • uncle - CA kidney 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
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
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
…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
Recommendations for Jane’s family • Jane’s paternal family history is suggestive of 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 HNPCC 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.
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
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
Potential Benefits: Avoidance of unnecessary clinical interventions Emotional - relief Children can be reassured May avoid higher insurance premiums Potential Risks: Adverse psychological reaction (i.e. survivor guilt) Dysfunctional family dynamics Complacent attitude to health Risks/Benefits/Limitations of genetic testing?Negative test result
Potential Benefits: Future research may clarify test results Importance of positive health behaviour can be reinforced Some relief Higher insurance premiums may be avoided Potential Risks: Continue clinical inventions which may carry risks Complacent attitude to health Uncertainty Continued anxiety Higher insurance premiums may not be reduced Risks/Benefits/Limitations of genetic testing?Uninformative test result
What is the benefit of genetic testing?Can anything be done to change risk /outcome? • Patients with HNPCC: • Colonoscopy beginning age 20 or 10 years younger than youngest CRC or adenomatous polyp diagnosis, whichever comes first • I recommendation • Subsequent colonoscopy every 1-2 years at least q3 years • B recommendation • Educate re symptoms of uterine cancer Johnson et al. Dis colon rectum 2006; 49:80-95
What is the benefit of genetic testing?Can anything be done to change risk /outcome? • Evidence for screening in HNPCC: • Cohort study of CRC screening – 15 yr F/U • Subgroup of HNPCC 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% • No evidence for screening for other cancers (i.e. uterine) • investigate irregular vaginal bleeding Jarvinin et al Gastroenterology 2000
What is the benefit of genetic testing?Can anything be done to change risk/outcome? • Patients with FAP: • Sigmoidoscopy every one to two 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 a year after polyps emerge
Management of Mutation Carriers Consider… • Psychological support to assist with: • adjusting to new information • making decisions regarding management • addressing family issues, self concept • dealing with future concerns i.e. child bearing • Stress management • Support group
Management of Mutation Carriers Consider… • Additional psychosocial support for those with: • History of depression/anxiety • Poor coping skills • Family communication issues or challenges • Multiple losses in the family • Loss of parent at a young age • Recent loss • Multiple surgical procedures
Resources • The National Cancer Institute: • http://www.nci.nih.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: Nschofield@odyssey.on.ca
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?
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
Legend Colon Case 1
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
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
Legend Colon Endometrial Kidney Prostate Case 2
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 HNPCC-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 HNPCC) • 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
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
Legend Colon Crohn’s disease Case 3
Case 3 Answer: • Low Risk for Hereditary CRC but still at increased Risk of CRC • Personal history of inflammatory bowel disease • Management: • Seek advice from gastroenterologist or surgeon for individuals with inflammatory bowel disease.
Legend Colon Case 4 Colon Ca Dx 74 Accident Alz -75 Aneurysm-65 A&W ↑Chol IDDM ID DM ↑Chol A&W A& W Colon CA Dx 52 A&W Your Patient A&W Asthma
Legend Colon Case 4
Case 4 Answer: • Population risk • Meets none of the other risk criteria • Still has a 1 in 16 lifetime risk of sporadic CRC • Management: • Beginning at Age 50: • Annual or biennial fecal occult blood testing (FOBT)AOR • Flexible sigmoidoscopy q 5yearsBOR • FOBT + flexible sigmoidoscopy q 5yearsIOR • Double contrast barium enema q 5 years OR • Colonoscopy q 10 yearsI A = Good evidence B = Fair evidence I = Insufficient evidence