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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
Funded by:
Sean Blaine BSc, MD, CCFP
Mount Sinai Hospital, University of Toronto
Stratford, Ontario
Ontario Women’s Health Council
Version: March 2006
The Genetics Education Project
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.
The Genetics Education Project
Outline
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Sporadic verses familial cancer
Hereditary colorectal cancer syndromes
Referral guidelines
Benefits, risks and limitations of genetic testing
Management
Case examples
The Genetics Education Project
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
The Genetics Education Project
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
The Genetics Education Project
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
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Proportion of Hereditary CRC
Hereditary 5%
- HNPCC ~ 2-5%
- FAP ~ <1%
Familial
15%
Sporadic
80%
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Knudson ‘two-hit’ Model
Sporadic Cancer
ONE HIT
(hit =mutation)
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
each copy of the gene
CANCER
The Genetics Education Project
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 nonmutated copy
CANCER
Two mutations one in
each copy of the gene
The Genetics Education Project
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
The Genetics Education Project
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
The Genetics Education Project
Autosomal Dominant Inheritance
Legend
Colon Cancer
bb
Bb
Bb
Susceptible
CRC gene
B: CRC gene
with mutation
Unaffected
b: normal
CRC gene
bb
Population
Risk
Bb
bb
Population
Affected with
Risk
Colon cancer
The Genetics Education Project
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.
The Genetics Education Project
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
The Genetics Education Project
Cancer Risk in Individuals with HNPCC to Age 70
Compared to the General Population
Cancer
General
Population Risk
HNPCC
Risk
Mean Age of Onset
In HNPCC
Colon
7%
70-80%
45 years
Endometrium
2.3%
20-60%
46 years
Stomach
<1%
13-19%
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%
1-2%
49 years
Brain / CNS
<1%
1-4%
50 years
from: http://www.genetests.org
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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.
The Genetics Education Project
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
Age
Individuals with colon
cancer
21
7%
45
85%
50
93%
From: http://www.genetests.org
The Genetics Education Project
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
The Genetics Education Project
Red Flags for hereditary colorectal cancer
– consider referral to genetics
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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
The Genetics Education Project
Risk of Developing Colorectal Cancer
Family History
Relative Risk
for CRC
Absolute Risk of
CRC by age 79
No family history
1 FDR with CRC
>1 FDR with CRC
1
2
4
4%
9%
16%
1 FDR Dx <45 yrs
1 FDR Dx CRC
adenoma
4
2
15%
8%
From: http://www.nci.nih.gov
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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
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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
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Jane’s Family Pedigree
LEGEND
Kidney
Colon
Endometrial
Breast
Accident
Mary
Dx 45 CA
A&W
Endometrial
Dx 68 CA Colon
Linda Dx 38
CA - colon
Stroke
Nat Causes
Bob Dx 56 Steve Dx 72
Kevin, 67
CA colon CA Kidney
A&W
Jeana Dx 40
Christa Dx 52
Ca-Endometrial CA – Colon
Paula Dx 66
CA- Br
Jane, 26
MI 72
A&W
A&W
A&W
A&W
A&W
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Jane was referred to genetics…
A genetics consultation involves:
 Detailed family history information
 Pedigree documentation
– Confirmation of cancer history: pathology reports/death
certificates
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Medical & exposure history
Empiric risk assessment
Hereditary cancer / genetic risk assessment
Psychological assessment
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…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
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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.
The Genetics Education Project
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
The Genetics Education Project
Risks/Benefits/Limitations
of genetic testing
Positive 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
The Genetics Education Project
Risks/Benefits/Limitations
of genetic testing?
Negative 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
The Genetics Education Project
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
 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
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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
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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
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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
The Genetics Education Project
Management of Mutation Carriers
Consider…
 Psychological support to assist with:
–
–
–
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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
The Genetics Education Project
Management of Mutation Carriers
Consider…
 Additional psychosocial support for those with:
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–
–
–
–
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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
The Genetics Education Project
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
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Case Examples
The Genetics Education Project
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?
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Case 1
Legend
Colon
↑Chol
A& W
↑Chol
Accident
‘Old Age’-82
Aneurysm-65
A&W
Your Patient
↑Chol
A&W
Colon CA
Dx 34
Asthma
A&W
Alz -75
ID DM
A&W
The Genetics Education Project
Case 1
Legend
Colon
The Genetics Education Project
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
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Legend
Colon
Case 2
Endometrial
Kidney
Prostate
↑Chol
Colon Ca
Dx 49
Endometrial
Ca Dx 33
Prostate Ca
Dx 72
Kidney Ca
Dx 65
Aneurysm-65
A&W
Colon Ca Dx 50
Your Patient
A&W
IDDM
Asthma
A&W
Alz -75
ID DM
A&W
The Genetics Education Project
Case 2
Legend
Colon
Endometrial
Kidney
Prostate
The Genetics Education Project
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 HNPCCassociated 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
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Legend
Case 3
Colon
Crohn’s
disease
↑Chol
A& W
A&W
Accident
Colon Ca
Dx 74
Aneurysm-65
A&W
↑Chol
A&W
Your Patient
Crohn’s disease
IDDM
Asthma
A&W
Alz -75
ID DM
A&W
The Genetics Education Project
Case 3
Legend
Colon
Crohn’s
disease
The Genetics Education Project
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.
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Case 4
Legend
Colon
Colon Ca
Dx 74
Aneurysm-65
↑Chol
A& W
Colon CA
Dx 52
A&W
Your Patient
Accident
↑Chol
A&W
IDDM
Asthma
A&W
Alz -75
ID DM
A&W
The Genetics Education Project
Case 4
Legend
Colon
The Genetics Education Project
Case 4
Answer:
 Population risk
 Meets none of the other risk criteria
 Still has a 1 in 16 lifetime risk of sporadic CRC
A = Good evidence
 Management:
B = Fair evidence
– Beginning at Age 50:
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I = Insufficient evidence
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
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Legend
Case 5
Colon
Lung
Lung Ca Dx 74
NON-smoker
Lung Ca Dx 43
Mesothelioma A&W
Smoker
Dx 45 Smoker
Chronic cough
Accident
Aneurysm-65
Chronic cough
Your Patient
A&W
Alz -75
Colon – CA
ID DM
Dx 61
A&W
Asthma
A&W
The Genetics Education Project
Case 5
Legend
Colon
Lung
The Genetics Education Project
Case 5
Answer:
 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:
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A = Good evidence
B = Fair evidence
I = Insufficient evidence
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
The Genetics Education Project
Legend
Case 6
Colon CA
Lung CA
Lung Ca Dx 74
Smoker
A&W
A&W
A&W
Accident
Aneurysm-65
A&W
Your Patient
A&W
A&W
Colon Ca Dx 42 A&W
~1000
polyps
Asthma
Alz -75
ID DM
Colon CA Dx 32
The Genetics Education Project
Case 6
Legend
Colon CA
Lung CA
The Genetics Education Project
Case 6
Answer:
 High risk for hereditary CRC
 >10 colorectal adenomatous polyps
– Personal history or
– 1st or 2nd degree relative (suggestive of FAP)
 Management:
– Suggestive of FAP:
 Seek advice from a colorectal specialist
– Offer referral to hereditary CRC/ Genetics Clinic
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Committee
 June 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 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
The Genetics Education Project
References
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Mitchell RJ, Farrington SM, Dunlop MG, Campbell H. Mismatch repair
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The Genetics Education Project
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Lightning bolt photo credit:
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The Genetics Education Project
References
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The Genetics Education Project
References
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Accessed June 21, 2005.
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carriers. Familial Cancer 2001; 1: 57-60.
The Genetics Education Project
References
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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
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HJ.Life-time risk of different cancer in the hereditary non-polyposis
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and endometrial cancer for carriers of hMLH1 and hMSH2 gene:
correction for ascertainment. J Med Genet 2005; 42:491-496.
The Genetics Education Project
References
21. Solomon C, Burt RW Familial adenomatous polyposis.
www.genetests.org. Last updated September 20, 2004, accessed July 22,
2005.
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guide to referral of patients with family history of cancer to a familial
cancer genetics clinic or genetics clinic. Ontario Medical Review 2001;
68(10):24-29.
23. Vasen HFA, Watson P, Mecklin J-P, Lynch, International Collaborative
Group on HNPCC. New clinical criteria for hereditary nonpolyposis
colorectal cancer (HNPCC, Lynch syndrome) proposed by the
International Collaborative Group on HNPCC. Gastroenterology 1999;
116:1453-1456.
24. http://www.nci.nih.gov/cancertopics/pdq/genetics/colorectal/healthprofes
sional#Section_12 Assessed on June 22, 2005.
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References
25. Johns LE, Houlston RS A systematic review and meta-analysis of familial
colorectal cancer risk. Am J Gastroenterol. 2001; 96:2992-3003.
26. Leddin D, Hunt R, Champion M, Cockeram A, Flook N, Gould M, Kim
Y-I, Love J, Morgan D, Natsheh S, Sadowski D, for the Canadian
Association of Gastroenterology and the Canadian Digestive Health
Foundation committee on colorectal cancer screening. Can J
Gastroenterologgy 2004;18:93-99.
27. Johnson PM, Gallinger S, McLeod RS. Surveillance colonoscopy in
individuals at risk for hereditary nonpolyposis colorectal cancer: an
evidence based review. Dis Colon Rectum 2005; 49:80-95.
28. Jarvinen HJ, Aarnio M, Mustonen H, Aktan-Collan K, Aaltonen LA,
Peltomaki P, de la Chapelle A. Controlled 15-year trial on screening for
colorectal cancer in families with hereditary nonpolyposis colorectal
cancer. Gastroenterology 2000; 118:829-834.
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References
29. Dove-Edwin I, Sasieni P, Adams J, Thomas HJW Prevention of colorectal
cancer by colonoscopic surveillance in individuals with a family history
of colorectal cancer: a 16 year, prospective, follow-up study. BMJ. 2005;
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Extra Slides
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HNPCC and Endometrial Cancer
 Risk to develop endometrial cancer is 20 – 60% by age 70
 Median age of diagnosis 46 years
 One small study of sporadic vs. HNPCC endometrial cancer
showed no significant difference in 5 year survival rate (88%)
 No consensus on tumour pathology – studies under way
 Screening recommendations beginning at age 25 – 35:
– Transvaginal ultrasound
– Endometrial sampling
 Risk Reducing surgery:
– Insufficient evidence to recommend
– Women can be counselled that risk-reducing hysterectomy and bilateral
salpingo-oophorectomy is an option.
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What is Microsatellite Instability (MSI)?
Microsatellites are repetitive segments of DNA
The same number of repeats are present
in every cell
Microsatellite Instability:
Normal microsatellite
with 2 repeats
The number of microsatellite repeats differs
between normal cells/tissue and tumour
cells/tissue
MSI is a pathology finding specific
to HNPCC colon tumours
Normal tissue
2 repeats
Tumour tissue
with MSI variable
repeat size 5 & 3
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Pathology & Genetic Evidence for Increased
Risk of Hereditary CRC
 Principle: Mutations of the genes MSH2, MLH1 and MSH6
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
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Pathology and Genetic Evidence for Increased
Risk of Hereditary Colorectal Cancer


Colonic ademoma or other HNPCC 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 or MSH6 and/or
2. Show evidence of genetic instability of small repetitive
DNA sequences (microsatellites) when compared to
normal tissue.
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