hereditary colorectal cancer
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Hereditary Colorectal CancerPrepared by: June C Carroll MD, CCFP, FCFP
Sydney G. Frankfort Chair in Family MedicineMount Sinai Hospital, University of Toronto
Andrea Rideout MS, CGC, CCGCCertified Genetic CounsellorProject Manager – The Genetics Education Project
Sean Blaine BSc, MD, CCFPMount Sinai Hospital, University of TorontoStratford, Ontario
Funded by: Ontario Women’s Health Council
Version: January 2010
Acknowledgments Reviewers: Members of The Genetics Education Project
(see slide 51) + Kara M. Semotiuk, MS, (C)CGC Genetic CounsellorHeidi Rothenmund, MS, (C)CGC Genetic CounsellorFamilial 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
CancerAll 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
damagedCell 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:
Causes unknown – multifactorial Interaction of many factors: age, environment, lifestyle,
chance, unknown factors
Sporadic cancer generally has a later onset
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
Proportion of Hereditary CRC
Sporadic 80%
Familial ~15%
Hereditary ~5%Lynch syndrome ~ 2-5%
FAP ~ <1%
Knudson ‘two-hit’ Model
Sporadic Cancer
Birth: Two non-mutated copies of the gene
One mutation in one gene; Second gene non-mutated
ONE HIT
(hit=mutation)
SECOND HIT
Two mutations - one in each gene
CANCER
Knudson ‘two-hit’ ModelHereditary Cancer
Birth: One mutation in one gene; Second gene non-mutated
ONE HIT
(hit=mutation)
SECOND HIT
Two mutations - one in each 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 Generally have a family history of cancer
Hereditary cancer is less common in the general population than sporadic cancer
Inherited Colorectal CancerTwo 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 cancerPrevalence of 1 in 8,000 – 14,000*
Autosomal dominant inheritance
*Prevalence depends on population
bb Bb
Bb bb Bb bb
CRC mutation
SusceptibleCRC gene
Autosomal Dominant Inheritance
Population Risk
Population Risk
SusceptibleCRC gene
Unaffected
Legend
B: CRC gene with mutation
b: normal CRC gene
Colorectal cancer genes…
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.
when mutated
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 cancerMore aggressive, proximal, right sided tumoursRisk for extra-colonic tumoursDistinct tumour pathology
Cancer Risk in Individuals with Lynch syndrome (HNPCC) to Age 70 Compared to General Population
Cancer General
Population Risk
Lynch syn.
Risk
Mean Age of Onset in Lynch
Colon 7 % 80% 45 years
Endometrium 2.7% 20-60% 46 years
Stomach <1% 11-19% 56 years
Ovary 1.5% 9-12% 42.5 years
Hepatobiliary tract
<1% 2-7% 54 years
Urinary tract <1% 4-5% ~55 years
Small Bowel <1% 1-4% 49 years
Brain / CNS <1% 1-3% 50 years
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 >10 but <100 polyps.
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
Age Individuals with colon cancer
21 7%
45 87%
50 93%
From: http://www.genetests.org
Consequences of FAP
~50-90% develop small bowel polypslifetime 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 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 genetic testing
Risk of Developing Colorectal Cancer
Family History Relative Risk
for CRC
Absolute Risk of CRC by age 79
No family history 1 4%
1 FDR with CRC 2 9%
>1 FDR with CRC 4 16%
1 FDR Dx <45 yrs 4 15%
1 FDR Dx CRC adenoma
2 8%
From: http://www.cancer.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 ureter age 72uncle - CA colon age 56aunt - double primary: endometrial CA
age 45, colon CA age 681 cousin - endometrial CA age 402 cousins - both have colon CA
Jane’s Family PedigreeLEGEND
Kidney
Colon
Endometrial
Breast
Jane, 26Linda Dx 38 CA - colon
Jeana Dx 40 Ca-Endometrial
Christa Dx 52CA – Colon
Mary
Dx 45 CA Endometrial
Dx 68 CA Colon
Bob Dx 56CA colon
Steve Dx 72CA Kidney
Paula Dx 66CA- Br
MI 72
Accident Nat Causes Stroke A&W
A&W A&WA&W
A&W A&W
Kevin, 67A&W
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 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
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
Risks/Benefits/Limitations of genetic testingPositive test result
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 testing? True Negative test resultPotential 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? Uninformative test result
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
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.
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
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
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
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.
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
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 detectedColectomyAnnual colonoscopy if colectomy is delayed
more than 1 year after polyps emerge
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 managementAddressing family issues, self concept, body
imageDealing with future concerns
Referral to support groups
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
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, President16 Redford Road CanadaLondon, ON N5X 3V5Email: wschofield@odyssey.on.ca
Case Examples
Assessing the Risk for Hereditary CRCUsing the Canadian Cancer Society triage card (below), what category of risk do the following family histories fit into?
Case 1
Alz -75
↑Chol
A&W ↑Chol Colon CA
Dx 34
Aneurysm-65
A&W
AsthmaA&WYour Patient
Accident‘Old Age’-82
ID DM
Colon
Legend
A& W↑Chol
A&W
Case 1
Colon
Legend
Case 1Answer: 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
Case 2
Alz -75
Endometrial Ca Dx 33
A&W Colon Ca Dx 50 IDDM
Aneurysm-65
A&W
AsthmaA&WYour Patient
Prostate Ca
Dx 72Kidney Ca
Dx 65
ID DMColon CaDx 49
↑Chol
A&W
Colon
Endometrial
Kidney
Prostate
Legend
Case 2
Colon
Endometrial
Kidney
Prostate
Legend
Case 2Answer: 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
Case 3
Alz -75
A&W
A&W ↑Chol IDDM
Aneurysm-65
A&W
AsthmaA&WYour Patient
Crohn’s disease
AccidentColon Ca
Dx 74
ID DMA& W↑Chol
Legend
Colon
Crohn’s
disease
A&W
Case 3
Legend
Colon
Crohn’s
disease
Case 3Answer: 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.
Case 4
Alz -75
Colon CA
Dx 52
A&W ↑Chol IDDM
Aneurysm-65
A&W
AsthmaA&WYour Patient
AccidentColon Ca
Dx 74
ID DM
Colon
Legend
A& W↑Chol
A&W
Case 4
Colon
Legend
Case 4Answer: 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)A OR Flexible sigmoidoscopy q 5yearsB OR FOBT + flexible sigmoidoscopy q 5yearsI OR Double contrast barium enema q 5 years OR Colonoscopy q 10 yearsI
A = Good evidenceB = Fair evidenceI = Insufficient evidence
Case 5
Alz -75
Chronic cough
A&WMesothelioma Dx 45 Smoker
A&W
Aneurysm-65
AsthmaA&WYour Patient
AccidentLung Ca Dx 74
NON-smoker
ID DMChronic coughLung Ca Dx 43Smoker
A&W
Colon
Lung
Legend
Colon – CA
Dx 61
Case 5
Colon
Lung
Legend
Case 5Answer: Population risk for CRC Patient’s family worked in a shipyard insulating
pipes Asbestos exposure increases risk of lung and
mesothelioma cancers High incidence of lung cancer due to common
environment exposures Management:
Beginning at Age 50: Annual or biennial FOBTA OR Flexible sigmoidoscopy q 5yearsB OR FOBT + flexible sigmoidoscopy q 5yearsI OR Double contrast barium enema q 5 years OR Colonoscopy q 10 yearsI
A = Good evidenceB = Fair evidenceI = Insufficient evidence
Case 6
Alz -75
A&W Colon Ca Dx 42
~1000
polyps
Aneurysm-65
AsthmaA&WYour Patient
AccidentLung Ca Dx 74
Smoker
ID DMA&WA&W
Colon CA Dx 32
A&W
Legend
Colon CA
Lung CA
A&W
A&W
Case 6
Legend
Colon CA
Lung CA
Case 6Answer: High risk for hereditary CRC >10 colorectal adenomatous polyps
Personal history or1st or 2nd degree relative (suggestive of FAP)
Management:Suggestive of FAP:
Seek advice from a colorectal specialist
Offer referral to hereditary CRC/genetics clinic
The Genetics Education Project Committee June C Carroll MD CCFP Judith Allanson MD
FRCP FRCP(C) FCCMG FABMG
Sean Blaine MD CCFP Mary Jane Esplen PhD
RN Sandra Farrell MD
FRCPC FCCMG Judy Fiddes Gail Graham MD FRCPC
FCCMG Jennifer MacKenzie MD
FRCPC FAAP FCCMG
Wendy Meschino MD FRCPC FCCMG
Joanne Miyazaki Andrea L. Rideout MS
CGC CCGC Cheryl Shuman MS CGC Anne Summers MD
FCCMG FRCPC Sherry Taylor PhD
FCCMG Brenda Wilson BSc MB
ChB MSc MRCP(UK) FFPH
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6. Lightning bolt photo credit: http://www.ghouli.com/articles/sp/mainstream_4b.htm
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Harkonen N, Julkunen R, Kangas E, Ojala S, Tulikoura J, Valkamo E, Jarvinen H, Jukka-Pekka M, Aaltonen L, de la Chapelle A. Population-based molecular detection of hereditary nonpolyposis colorectal cancer. J Clin Oncol 2000;18: 2193-2200.
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References13. Vasen HFA, Wijnen JT, Menko FH Kleibeuker JH, Taal BG,
Griffioen G, Nagengast FM, Meijer-Heijboer EH, Bertario L, Varesco L, Bisgaard M_L, Mohr J, Fodde R, Khan PM. Cancer risk in families with hereditary colorectal cancer diagnosed by mutational analysis. Gastroenterology 1996; 110:1020-1027.
14. The Canadian Cancer Society, National Cancer Institute of Canada, Statistics Canada, Provincial/Territorial Cancer Registries, Public Health Agency of Canada. Canadian Cancer Statistics 2005 http://www.cancer.ca/vgn/images/portal/cit_86751114/48/28/401594768cw_2005stats_en.pdf Accessed June 21, 2005.
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Jarvinen HJ, Meckllin JP, Macrae F, St. John DJB, Bertario L, Fidalgo P, Madlensky L, Rozen P, and the International Collaborative Group on HNPCC. Characteristics if small bowel carcinoma in hereditary nonpolyposis colorectal carcinoma. Cancer 1998; 83:240-244.
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19. Aarnio M, Mecklin J-P, Aaltonen LA, Nystrom-Lahti M, Jarvinen HJ.Life-time risk of different cancer in the hereditary non-polyposis colorectal cancer (HNPCC) syndrome. Int J Cancer 1995; 64:430-433.
20. Quehenberger F, Vasen HFA, van Houwelingen HC. Risk of colorectal and endometrial cancer for carriers of hMLH1 and hMSH2 gene: correction for ascertainment. J Med Genet 2005; 42:491-496.
References21. Burt RW, Jasperson KW Familial adenomatous polyposis.
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Extra Slides
What is Microsatellite Instability (MSI)?
Microsatellites are repetitive segments of DNA
The same number of repeats are present
in every cell
Microsatellite Instability:The number of microsatellite repeats differs between normal cells/tissue and tumour cells/tissue
Normal microsatellite with 2 repeats
Normal tissue2 repeats
Tumour tissue with MSI variable repeat size 5 & 3MSI is a pathology finding specific
to Lynch syndrome colon tumours
Pathology & Genetic Evidence for Increased Risk of Hereditary CRC Principle: Mutations of the genes MSH2, MLH1, MSH6 and PMS2
increase the rate of genetic mutation in human cells. Small repetitive sequences (microsatellites) are very susceptible to
increases in the mutation rate. These repetitive sequences can be surveyed to see if there are
differences in their sequence between the normal and tumor tissues from an individual.
If changes are seen the tumor can be referred to as showing “microsatellite instability”.
Typically there is good concordance between seeing that a tumor is by immunohistochemistry immunodeficient for one of these gene products and the finding of microsatellite instability.
Observing either one or both in a tumor increases the likelihood a familial mutation is present
Pathology and Genetic Evidence for Increased Risk of Hereditary Colorectal Cancer Colonic ademoma or other Lynch syndrome
associated cancers can be found in the laboratory to have one or both of the following properties which increase the likelihood a familial mutation is responsible.
The tumors: 1. Are deficient for immunohistochemical staining for
the proteins MSH2, MLH1, MSH6 and/or PMS2
2. Show evidence of genetic instability of small repetitive DNA sequences (microsatellites) when compared to normal tissue.
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