1. 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
Stratford, Ontario
Funded by: Ontario Women’s Health Council
Version: March 2006
Slide 1:
Title

2. 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.
Slide 2:
Acknowledgements
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
Slide 3:
Outline

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
Slide 4:
Cancer1
All cancer is genetic because it is caused by an accumulation of mutations in the cell’s genetic code (genes) that leads to tumour development.
Threshold effect: During the cell cycle, as the cell goes through DNA replication and mitosis, mistakes or mutations occur in the cell’s genetic code. These mistakes are normally corrected by a class of genes known as DNA mismatch & repair genes. Our cells have a series of checks and balances to maintain the rate of new cell growth and cell death. This balance is maintained by several classes of genes: tumour suppressors, oncogenes, DNA mismatch & repair genes.
A cell accumulates mutations either by chance or environmental exposures or due to an inherited defect in the normal DNA repair system.
When there are too many changes in the cell’s genetic code, the cell is unable to repair the mutations and/or regulate cell growth. At this point, irreversible changes in the cell’s DNA lead to an atypical cell - with uncontrolled proliferation, this can lead to the development of a tumor.

5. Sporadic Cancer All cancer arises from changes in genes….
But NOT all cancer is inherited
Most CRC is sporadic ~ %
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
Slide 5:
Sporadic Cancer
In cases of sporadic cancer, mutations in the genes that regulate and maintain the cell cycle and DNA integrity occur after birth
Colorectal cancer (CRC) is multifactorial – it is caused by the interaction of many factors such as age, lifestyle, environmental exposures, genetic or chance/unknown factors.
Sporadic cancer generally has a later onset (after 50 years of age) than inherited cancer.

6. 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
Slide 6:
Clustering of Cancer in Families
Approximately 20% of people with CRC have a family history.
~ 15 % of CRC is familial – these people have a first- or second-degree relative who has also been diagnosed with CRC. These cases could be due to:
Common (unidentified) susceptibility genes
Common environment exposures
Common lifestyle
Chance: Approximately 1 in 14 or 7% of Canadian men and 1 in 6 or 6 % of Canadian women will develop CRC in their lifetime.2
~ 5 % of CRC is hereditary – in these cases a person is born with an inherited predisposition to cancer. Majority is hereditary nonpolyposis colorectal cancer (HNPCC) and <1% is due to familial adenomatous polyposis (FAP).3,4,5 Others include rare genetic syndromes associated with an increased risk of cancer.

7. Proportion of Hereditary CRC
- HNPCC ~ 2-5%
- FAP ~ <1%
Familial
15%
Slide 7:
Proportion of colorectal cancer due to sporadic or inherited factors
Graph:
Sporadic: 80%
Familial: 15%
Hereditary 5%: HNPCC 2-5% and FAP <1%
Sporadic80%

8. Knudson ‘two-hit’ Model Sporadic Cancer
ONE HIT
(hit =mutation)
Birth: Two non-mutated copies of the gene
SECOND HIT
Slide 8:
Knudson’s ‘Two-Hit’ Hypothesis – Sporadic Cancer 1, 6
Knudson proposed the existence of cancer susceptibility genes that are inherited in an autosomal dominant manner.
For sporadic cancer; susceptibility genes are normal or non-mutated at birth.
Throughout a person’s lifetime they may acquire a ‘hit’ or a mutation in a cancer susceptibility gene.
Later in life if a person is exposed to a second ‘hit’ or mutation in a cancer susceptibility gene, this can lead to cancer.
These acquired mutations are somatic; they are not present in every cell and are not inherited.
One mutation in one copy of the gene; One non-mutated copy
Two mutations one in each copy of the gene
CANCER

9. Knudson ‘two-hit’ Model Inherited cancer
Born with one hit
(hit = mutation)
Birth: Two non-mutated copies of the gene
SECOND HIT
Slide 9:
Knudson’s ‘Two-Hit’ Model – Inherited Cancer Predisposition 1, 4
If a person is born with a germline mutation in a cancer susceptibility gene; they are born with one ‘hit.’ Germline mutations are present at conception and are in every cell of the body and can be inherited. So in the case of inherited colorectal cancer syndrome, the first hit is inherited in an autosomal dominant manner and is present in every cell in the body.
The second ‘hit’ is a somatic mutation – a mutation present only in the cell that acquired this mutation. So in the case of inherited colorectal cancer syndrome the second hit is not inherited and occurs by chance in a single cell – possibly due to exposure to an environmental toxin etc.
If a person has inherited a mutation in a cancer predisposition gene like the genes involved in HNPCC or FAP, generally the age of onset of cancer is earlier, as it would take less time to acquire a second ‘hit’ than someone who has cancer due to two random (somatic) hits.
Birth: One mutation in one copy of the gene; One non-mutated copy
Two mutations one in each copy of the 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
Hereditary cancer is less common in the general population than sporadic cancer
Slide 10:
Compared to sporadic cancer hereditary cancer has…
Sporadic and hereditary cancers have different genetic pathways leading to the development of cancer. This leads to general differences in their clinical presentation.

11. Inherited Colorectal Cancer
Two common syndromes:
Hereditary Non-Polyposis Colon Cancer (HNPCC)
~2 - 5% of colorectal cancer
Prevalence 1 in ,000
Familial Adenomatous Polyposis (FAP)
<1% of colorectal cancer
Incidence of 1 in 8,000 – 14,000
Autosomal dominant inheritance
Slide 11:
Inherited Colorectal Cancer
Hereditary Non-Polyposis Colon Cancer (HNPCC)
Prevalence (number of cases of a disease existing in a given population at a specific period in time):
1 in 3,0007 (this may be an under estimate of the prevalence)
Founder effect in Newfoundland, Italian-Quebec families, Danish and Finnish.3
Familial Adenomatous polyposis (FAP)
Incidence (number of new cases) 1 in 8,000 – 14,000 8

12. Autosomal Dominant Inheritance
Legend
B: CRC gene with mutation
b: normal CRC gene
Colon Cancer
Unaffected bb Bb
Slide 12:
Autosomal Dominant Inheritance
All of the susceptibility genes for HNPCC are inherited in an autosomal dominant pattern, meaning that only 1 abnormal copy of the HNPCC genes is needed to increase an individual’s predisposition to colon, endometrial and other HNPCC spectrum cancers.
The APC gene that causes FAP is also inherited in an autosomal dominant manner; this gene is ~100% penetrant meaning that virtually everyone who inherits the gene will develop colon cancer.
The capital “B” in this diagram is the cancer predisposition mutation. The normal copy of the gene is represented by the lower case “b”.
There is a 50:50 risk for an affected parent to pass on this mutation to their children of either sex. bb Bb Bb bb
Population
Risk
Affected with
Colon cancer
Susceptible
CRC gene
Population
Risk

13. 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.
Slide 13:
Colorectal cancer genes… when mutated
HNPCC:
Mutations in DNA repair genes lead to an accumulation of somatic mutations that may result in malignancy.
The nature of mutated DNA repair genes leads to microsatellite instability in the tumour, which can be diagnosed on pathological examination. This is a hallmark of HNPCC. Microsatellites are repetitive segments of DNA. Microsatellite instability is the presence of a discrepancy between the size of microsatellites in DNA from tumor tissue compared to non-tumour tissue from the same person. For more information on microsatellites see ‘Extra Slides’ at the end of this slide show.
90% of CRC tumours from HNPCC patients show microsatellite instability compared with only 10-15% of sporadic cancers. 8
Some groups have proposed that all tumours showing microsatellite instability should be screened for the common HNPCC mutations. 10

14. 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
Slide 14:
Hereditary Nonpolyposis Cancer (HNPCC)
HNPCC genetically heterogeneous - 5 genes:
MLH1 & MSH2 (most common), MSH6, PMS1 & PMS2
Autosomal dominant
High penetrance 70-80%
Characterized by:11
Early onset of diagnosis (average age 45 rather than 69)12
More aggressive adenomas
More proximal or ‘right sided’ CRC tumours (70% before splenic flexure)
Tumours show microsatellite instability on pathology exam
Risk for extra-colonic tumors

15. Cancer Risk in Individuals with HNPCC to Age 70 Compared to the General Population
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
2-7%
54 years
Urinary tract
4-5%
~55 years
Small Bowel
1-2%
49 years
Brain / CNS
1-4%
50 years
Slide 15:
Cancer Risk in Individuals with HNPCC to Age 70 Compared to the General Population 12-19
Mutations in MSH2 are more often associated with extra-colonic cancer than mutations in MLH1. Families who have mutations in MSH6 may have an excess of endometrial cancer compared to colon cancer.
Note transitional cell (urothelial) cancer is the specific subtype of renal cancer that is associated with HNPCC.
The figures in this chart are based on studies of high-risk families.
A recent study of low risk families proposes that the risk for colorectal cancer and endometrial cancer is much lower than previously reported. In this study, the risk for colorectal cancer in men by age 70 was 27%, for women 22% and the risk for endometrial cancer was 32%.20
In addition to family history, other factors that affect a mutation carrier’s risk of developing cancer include:
Variable penetrance – Some HNPCC mutation carriers may never get cancer. FAP is virtually ~100% penetrant.
Environmental & genetic modifiers
Nature of the mutation
Variable age of onset – Some may develop cancer very early i.e. 30’s, others may have a late onset i.e. after age 50
from:

16. 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.
Slide 16:
Familial Adenomatous Polyposis 8
High penetrance ~100% for classic FAP

17. Individuals with colon cancer
Consequences of FAP
Colorectal adenomatous polyps begin to appear at an average age of 15 years (range 7-36 years)
Average age at diagnosis: years, when >95% have polyps
Age
Individuals with colon cancer 21 7% 45
85% 50
93%
Slide 17:
Consequences of FAP (1) 8
From:

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
Slide 18:
Consequences of FAP (2) 21
Other: osteomas, dental abnormalities, congenital hypertrophy of the retinal pigment epithelium (CHRPE)

19. 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
Slide 19:
Red Flags for hereditary colorectal cancer – consider referral to Genetics 22
A good reference for referral criteria to hereditary cancer clinics and criteria for genetic testing: Predictive Cancer Genetics Steering Committee. Ontario physicians’ 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.
Please note these guidelines are currently under revision

20. 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
15%
1 FDR Dx CRC adenoma 8%
Slide 20:
Risk of developing colon cancer 24,25
Taking an accurate family history is important to determine your patient’s risk of many common conditions like CRC.
Data in this chart was derived from meta-analyses of case control and cohort studies, using data from cancer family clinic patient populations.26
From:

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
Slide 21:
Case: Jane
Demographics

22. 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
Slide 22:
Case continued

23. Jane’s Family Pedigree
LEGEND
Kidney
Colon
Endometrial
Breast
Jane’s Family Pedigree
Accident
Nat Causes
Stroke
A&W
Mary
Dx 45 CA Endometrial
Dx 68 CA Colon
Bob Dx 56
CA colon
Steve Dx 72
CA Kidney
Paula Dx 66
CA- Br
A&W
Kevin, 67
A&W
MI 72
A&W
A&W
Slide 23:
Case: Jane’s family history
Family history –3-generations, note both affected and unaffected family members, age at diagnosis, current age and whether affected members alive or deceased.
Note that circles denote females, squares denote males, and joining lines indicate a relationship such as spouse or sibs and a diagonal line means deceased.
Jane, a 26 year-old woman indicated by the arrow, is your patient; her mother was diagnosed with breast cancer at 66, no other known cases of cancer on her mother’s side of the family.
Jane’s father’s family: 1 uncle diagnosed with transitional cell/kidney cancer at 72 and a second uncle diagnosed with CRC at 56. An aunt with 2 primary cancers: one endometrial cancer at 45 and colon cancer at 68. Two of Jane’s first cousins were diagnosed with CRC and a third with endometrial cancer.
Drawing a pedigree assists in determining relationships i.e. are all affected on same side of family?
This family has four members affected with colon cancer in two generations, two of which were diagnosed <50 years of age plus two additional members with HNPCC – associated cancers.
Linda Dx 38
CA - colon
Jeana Dx 40 Ca-Endometrial
Christa Dx 52
CA – Colon
A&W
Jane, 26
A&W

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
Slide 24:
Jane was referred to genetics….
A genetics consultation involves 1
History: The patient’s family medical and exposure history may be taken by phone prior to the genetic counselling session; some genetics clinics might send the patient a detailed questionnaire by mail. This allows for patients to contact family members and clarify cancer diagnosis, age of onset and helps to obtain accurate family history information.
It is important to confirm family members’ diagnoses of cancer with pathology reports as the patient’s reported cancer site may turn out to be in a different organ/location.
Risk assessment: Based on the information collected, the patient will receive estimation of his/her risk of carrying a mutation in one of the HNPCC genes. Population risks and HNPCC carrier risks for cancer will also be discussed.
Genetic testing has implications not only for the patient’s health but also for their psychological well-being, insurability and for their family members. Therefore a psychological assessment is an important part of offering genetic testing.
Assessing the patient’s interest, motivation and readiness for genetic testing
Does the patient have the coping skills to deal with the results; do they have a support system? A history of psychological issues?
Has the patient considered the impact on family members?
Is the patient psychologically prepared to undergo testing?

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
Slide 25:
A genetics consultation involves 2
Eligibility: The family history is analysed to determine which family member should be offered testing first. The family member with the highest likelihood of carrying a mutation in one of the HNPCC genes is the family member who should be offered genetic testing first. This would usually be the youngest family member diagnosed with cancer. In Jane’s case this would be her paternal aunt with both colon and endometrial cancer.
The genetic testing procedure is described as well as the risks, benefits and limitations of testing.
Management recommendations are made following disclosure of results.

26. 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.
Slide 26:
Recommendations for Jane’s family
The history of cancer in Jane’s father’s family is suggestive of HNPCC. Note the multiple cases of early onset colon cancer and her paternal aunt with two primary cancers - endometrial and colon.
The most appropriate person in Jane’s family to offer genetic testing would be Jane’s aunt who has been diagnosed with two primary cancers. If her aunt does not agree to genetic testing then the youngest affected member would be the next person to approach.
If a mutation is identified in one of Jane’s family members then sequential testing of the family can proceed. Jane’s father can be tested and then Jane if he tests positive. If Jane’s father tests negative then there is no reason to offer Jane testing as she would not be at risk to carry a mutation.
If no mutation is identified then the family is still at increased risk for colon and possibly other HNPCC spectrum cancers.

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
Slide 27:
Results from Genetic Testing
POSITIVE: a deleterious mutation has been identified.
Your patient should be following high risk screening recommendations for colon cancer and for endometrial and ovarian cancer.
Consider referral for psychological support to help adjust to the diagnosis
If they have colon cancer then they are at risk for a second primary -either a second colon cancer or, in the case of HNPCC, other related cancers.
Patients with FAP should consider risk-reducing surgery.
NEGATIVE: interpretation depends on whether or not a deleterious mutation has been previously identified in the family.
If a deleterious mutation has been previously identified in the family, then this is the best result - a true negative - and your patient should follow population screening recommendations for colon cancer as they are still at risk for sporadic cancer.
If no deleterious mutation has been previously identified and your patient has cancer then the results are uninformative.
There may be a mutation in APC gene or the HNPCC genes that is not detectable by the current technology.
The family history of cancer may be caused by a yet to be discovered gene.
The family history of cancer may be due to chance or common environmental factors.
The family may have a rare genetic syndrome that has an associated increased risk for cancer.
VARIANT OF UNKNOWN SIGNIFICANCE: It is not known if the changes identified in your patient’s DNA are harmful or benign.
A patient may carry a variation in their APC gene or HNPCC genes. The variation may be a harmless polymorphism – a change in genetic code that will not alter the function of the APC or HNPCC proteins and therefore will not cause an increased risk for cancer but;
The patient still has an increased risk for cancer based on family history.
The family history of cancer may be due to chance or common environmental factors
The variant may really be a harmful mutation causing a predisposition to cancer. Studying other family members with cancer to see whether or not the mutation is tracking with cancer in the family may provide clarification for this family. For example if the variant is NOT found in a family with cancer then the variant may not be harmful.
The clinical significance of these variants may be clarified with further research.
Patient should still follow high risk screening recommendations.
The false positive rate of genetic testing for HNPCC is equal to the rate of sample mix up ~<1 in 10,000 and the false negative rate is very low.

28. 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
Slide 28:
Potential Risks/Benefits/Limitations of Genetic Testing 1
Positive Result: Benefits
Explains the pattern of cancer in the family and provides clinical information.
Clinical intervention may improve outcome (specific guidelines will be listed later)
Family members at risk can be identified and offered testing
May benefit from more intensive screening or clinical intervention if positive
Positive health behaviour can be reinforced
Reduces uncertainty – can move forward acceptance of the disease and consider options for management
Positive Result: Risks
Adverse psychological reactions
Anxiety, depression, grief, isolation, loss of control
Guilt or shame for passing it on to their children
Fear of disfigurement, of becoming a burden, of dying
Fatalistic attitude toward health
Family issues – some members may not want this information
Uncertainty - incomplete penetrance- some mutation carriers will never develop cancer
Unnecessary anxiety, interventions etc.
Possible discrimination: insurance, employment
Confidentiality issues
Surgical intervention (if taken) carries risk

29. Risks/Benefits/Limitations of genetic testing? Negative test result
Potential Risks:
Adverse psychological reaction (i.e. survivor guilt)
Dysfunctional family dynamics
Complacent attitude to health
Potential Benefits:
Avoidance of unnecessary clinical interventions
Emotional - relief
Children can be reassured
May avoid higher insurance premiums
Slide 29:
Potential Risks/Benefits/Limitations of Genetic Testing 2
Negative Result: Benefits
Avoidance of unnecessary clinical interventions i.e. no need to consider risk reducing surgery (colectomy).
Emotional - relief
Children can be reassured
May avoid higher insurance premiums
Negative Result: Risks
If a mutation was previously identified in the family and the patient’s result is negative, this is the best possible outcome. However the patient may still have adverse psychological reactions (uncommon):
Survivor guilt, isolation
Family dynamics – the patient may not feel they ‘belong’ to or feel accepted by the disease group (other family members who are at high risk for cancer and are acting as support for the other high-risk family members).
Patients may feel that their risk of developing cancer is zero and may be reluctant to participate in screening. – may become complacent

30. Risks/Benefits/Limitations of genetic testing
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
Slide 30:
Potential Risks/Benefits/Limitations of Genetic Testing 3
Uninformative result: Benefits
Some patients may experience relief that they do not carry a definite mutation. For others, the uncertainty may cause stress.
Discrimination/insurance issues may be avoided because the patient does not have a proven mutation or may not be avoided due to the unknown significance of the findings.
Higher insurance premiums may be avoided or may not be reduced – no data regarding Canadian insurance companies.
Uninformative result: Risks
Some patients may wish to continue high-risk screening or opt for surgical interventions.
Patient might stop taking an active role in their health care
Adverse psychological reactions – fear of uncertainty, frustration, family dynamics

31. What is the benefit of genetic testing
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
Slide 31:
What is the benefit to the patient of having genetic testing? 1
Can anything be done to change risk/outcome?
Canadian Association of Gastroenterology and the Canadian Digestive Health Foundation: Guidelines on colon cancer screening: 26
HNPCC: Colonoscopy every 1-2 years beginning at age 20 or 10 years younger than the earliest case in the family, whichever comes first.
Patients with HNPCC:
An evidence based review from 2005 supports surveillance with complete colonoscopy every 3 years - B recommendation. There is no evidence to support or refute more frequent screening. 27
Johnson et al. Dis colon rectum 2006; 49:80-95

32. What is the benefit of genetic testing
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 )
RR of death = 0.35 (95% CI )
15 yr survival 92% vs. 74%
No evidence for screening for other cancers (i.e. uterine)
investigate irregular vaginal bleeding
Slide 32:
What is the benefit to the patient of having genetic testing? 2
Can anything be done to change risk/outcome?
US Cancer Genetic Studies Consortium Recommendations: 11
Full colonoscopy to the cecum is recommended every 1 – 3 years beginning age 25 years.
Studies show a 65% reduction in mortality from CRC with regular colonoscopies in mutation positive individuals. 28
British study of patients at moderate and high risk for colon cancer based on family history:29
HNPCC patients with colonoscopies every 1 to 3 years had an estimated 72% reduction in mortality.
Individuals at moderate risk for colon cancer with colonoscopies at 5 year intervals had an 81% reduction in mortality.
Other cancers: There is no evidence to support screening for other cancers.
Annual screening for endometrial cancer beginning at age 25 to 35 years has been suggested. The optimal method of screening has not been determined – choices include endometrial aspirate or transvaginal ultrasound. – no evidence for benefit at this time 11
Other surveillance: ovarian cancer screening (serum CA-125 and transvaginal ultrasound) – no evidence of benefit at this time 11
Other groups have recommended screening for HNPCC associated tumours based on family history of those specific cancers. For a history of gastric cancer - screening can be done with esophagogastroduodenoscopy, for those with a history of cancer of renal pelvis or ureter - screening includes urinalysis, urine cytology, cytoscopy and ultrasound to evaluate the upper uroepithelial tract. 30
Jarvinin et al Gastroenterology 2000

33. What is the benefit of genetic testing
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
Slide 33:
What is the benefit to the patient of having genetic testing? 3 8,21
Can anything be done to change risk/outcome?
Canadian Association of Gastroenterology and the Canadian Digestive Health Foundation: Guidelines on colon cancer screening: 26
FAP: Sigmoidoscopy annually beginning at age years. Attenuated FAP: Colonoscopy annually beginning at age years.
Patients with FAP:
Non-steroidal anti-inflammatory drugs (NSAIDs).  Some NSAIDs have been shown to cause regression of adenomas in FAP and to decrease the number of polyps requiring ablation in the remaining rectum of persons who have had a subtotal colectomy. NSAID use before colectomy remains experimental.

34. 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
Slide 34:
Management of Mutation Carriers – Psychological 1
Referral to:
Psychologist, nurse-counsellor:
Can assist the patient make the best management decision for their situation and can help them adjust to their decision
Address emotional issues: self concept, guilt at having passed on mutation to children, dealing with risk of cancer.

35. 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
Slide 35:
Management of Mutation Carriers – Psychological 2
Women who test positive or negative for a mutation may benefit from additional support in these situations.

36. Resources The National Cancer Institute:
Gene Tests:
Colon Cancer Alliance:
Canadian Cancer Society:
Cancer Genetics Support Group of Canada (CHGSGC):
Contact Name: Nancy Schofield, President
16 Redford Road Canada
London, ON N5X 3V5
Slide 36:
Resources

37. Case Examples
Slide 37:
Case Examples

38. 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?
Slide 38:
Assessing the Risk of Hereditary Colorectal Cancer
These case examples are designed to accompany the Canadian Cancer Society Hereditary Colorectal Cancer triage/management cards. To order triage cards (at no cost), contact your local chapter of the Canadian Cancer Society.
For the pedigrees: the arrow denotes “Your Patient”, shaded circles or squares denote family members affected with cancer – for the specific type of cancer see the legend.

39. Case 1 Your Patient Colon Legend Accident Alz -75 Aneurysm-65
‘Old Age’-82
↑Chol
↑Chol
Colon CA
Dx 34
A&W
Slide 39:
Case 1
Pedigree:
Your patient’s mother diagnosed with colon cancer at 34 years of age.
A& W
A&W
ID DM
↑Chol
Your Patient
A&W
Asthma
A&W

40. Case 1 Legend Colon Slide 40: Case 1
Answer: Moderate risk for hereditary CRC
Colon
Legend

41. 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
Slide 41:
Case 1
Management

42. Case 2 Your Patient Colon Endometrial Kidney Prostate Legend
Prostate Ca
Dx 72
Kidney Ca
Dx 65
Aneurysm-65
Alz -75
↑Chol
Colon Ca
Dx 49
Colon Ca Dx 50
IDDM
A&W
Slide 42:
Case 2
Pedigree:
One 1st degree relative with colon cancer diagnosed at 50.
One second-degree relative diagnosed with colon cancer <50 years and one HNPCC-related cancer (kidney) >50 years.
One third-degree relative with HNPCC-related cancer (endometrial) diagnosed <50 years.
A&W
ID DM
Endometrial Ca Dx 33
Your Patient
A&W
Asthma
A&W

43. Case 2 Legend Colon Endometrial Kidney Prostate Slide 43: Case 2
Answer: High risk for hereditary CRC
Colon
Endometrial
Kidney
Prostate
Legend

44. 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
Slide 44:
Case 2
Management

45. Case 3 Your Patient Crohn’s disease Legend Colon Crohn’s disease
Aneurysm-65
Colon Ca
Dx 74
Accident
Alz -75
↑Chol
↑Chol
IDDM
A&W
Slide 45:
Case 3
Pedigree
Your patient has Crohn’s disease
One 2nd degree relative with colon cancer >50 years
A& W
A&W
ID DM
A&W
Asthma
A&W
Your Patient
Crohn’s disease
A&W

46. Case 3 Legend Colon Crohn’s disease Slide 46: Case 3
Answer: Low risk for hereditary CRC but still at increased risk of CRC
Legend
Colon
Crohn’s
disease

47. 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.
Slide 47:
Case 3
Management

48. Case 4 Your Patient Legend Colon Colon Ca Accident Aneurysm-65 Dx 74
Alz -75
↑Chol
↑Chol
IDDM
A&W
Slide 48:
Case 4
Pedigree
One 2nd degree relative with colon cancer >50 years
One 3rd degree relative with colon cancer >50 years
A& W
A&W
ID DM
Colon CA
Dx 52
Your Patient
A&W
A&W
Asthma

49. Case 4
Slide 49:
Case 4
Answer: Population risk for CRC
Colon
Legend

50. 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)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 evidence
B = Fair evidence
I = Insufficient evidence
Slide 50:
Case 4
Management

51. Case 5 Your Patient Colon Lung Legend Lung Ca Dx 74 NON-smoker
Accident
Aneurysm-65
Alz -75
Lung Ca Dx 43
Smoker
Chronic cough
Slide 51:
Case 5
Pedigree
One maternal 2nd degree relative with colon cancer >50 years.
Two paternal 2nd degree relatives with lung cancer (smoker) and mesothelioma (smoker) <50 years
One paternal 2nd degree relative diagnosed with lung cancer (non-smoker) >50 year.
A&W
Colon – CA
Dx 61
ID DM
Mesothelioma Dx 45 Smoker
A&W
Chronic cough
Your Patient
A&W
Asthma
A&W

52. Case 5 Legend Colon Lung Slide 52: Case 5
Answer Population risk for CRC
Colon
Lung
Legend

53. 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:
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
Slide 53:
Case 5
Management
A = Good evidence
B = Fair evidence
I = Insufficient evidence

54. Case 6 Your Patient Legend Colon CA Lung CA Lung Ca Dx 74 Smoker
Accident
Aneurysm-65
Alz -75
A&W
Colon Ca Dx 42
~1000
polyps
A&W
A&W
Slide 54:
Case 6
Pedigree:
One 1st degree relative with >1000 polyps <50 years
One 2nd degree relative with lung cancer (smoker)
A&W
ID DM
A&W
A&W
Your Patient
A&W
Asthma
Colon CA Dx 32

55. Case 6 Legend Colon CA Lung CA Slide 55: Case 6
Answer: High risk for hereditary CRC
Legend
Colon CA
Lung CA

56. 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
Slide 56:
Case 6
Management

57. The Genetics Education Project 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
Slide 57:
The Genetics Education Project Committee

58. References
Offit K Clinical Cancer Genetics: Risk Counseling and Management. Wiley-Liss, New York
Statistics from the Canadian Cancer Society: accessed on June 22, 2005.
Hampel H, Frankel WL, Martin E, Arnold M, Khanduja K, Kuebler P, Nakagawa H, Sotamaa K, Prior TW, Westman J, Panescu J, Fix D, Lockman J, Comeras I, de la Chapelle A. Screening for Lynch syndrome (hereditary nonpolyposis colorectal cancer). N Engl J Med 2005; 352:
Mitchell RJ, Farrington SM, Dunlop MG, Campbell H. Mismatch repair genes hMLH1 and hMSH2 and colorectal cancer: a huge review. Am J Epidemiol 2002; 156:
Slide 58:
References 1

59. References
Ponz de Leon M, Sassatelli R, Benatti P, Roncucci L. Identification of hereditary nonpolyposis colorectal cancer in the general population. The 6-year experience of a population-based registry. Cancer 1993; 71:
Lightning bolt photo credit:
Dunlop MG, Farrington SM, Nicholl I, Aaltonen L, Petersen G, Porteous M, Carothers. Population carrier frequency of hMSH2 and hMLH1 mutations. Br j Cancer 2000; 83:
American Gastroenterological Association (The Clinical Practice and Practice Review Committee). AGA technical review on hereditary colorectal cancer and genetic testing. Gastroenterology 2001;121:
Slide 59:
References 2

60. References
Salovaara R, Loukola A, Kristo P, Kaariainen H, Ahtola H, Eskelinen M, 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:
Wijnen JT Vassen HFA, Khan PM, Zwinderman AH, van der Klift H, Mulder A, Tops C, Moller P, Fodde R. Clinical findings with implications for genetic testing in families with clustering of colorectal cancer. N Engl J Med. 1998; 339:
Burke W, Petersen G, Lynch P, Botkin J, Daly M, Garber J, Khan MJE, McTiernan A, Offit K, Thompson E, Varricchio C for the Cancer Genetics Studies Consortium. Recommendations for follow-up care of individuals with an inherited predisposition to cancer. I. Hereditary nonpolyposis colon cancer. JAMA 1997; 277:
Lin K, Shashidaran M, Ternent C, Thorson AG, Blatchford GJ, Christensen MA, Lanspa SJ, Lemon SJ, Watson P, Lynch H. Colorectal and extracolonic cancer variations in MLH1/MSH2 hereditary nonpolyposis colorectal cancer kindreds and the general population. Dis Colon Rectum. 1998; 41:
Slide 60:
References 3

61. References
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:
The Canadian Cancer Society, National Cancer Institute of Canada, Statistics Canada, Provincial/Territorial Cancer Registries, Public Health Agency of Canada. Canadian Cancer Statistics Accessed June 21, 2005.
Kohlmann W, Gruber SB Hereditary nonpolyposis colorectal cancer. Gene Tests Reviews last updated February 5, Accessed June 21, 2005.
Watson P, Lynch HT Cancer risk in mismatch repair gene mutation carriers. Familial Cancer 2001; 1:
Slide 61:
References 4

62. References
Rodriquez-Bigas MA, Vassen HF, Lynch HT, Waston P, Myrhoj T, 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:
Aarnio M, Sankila R, Pukkala E, Salovaara R, Aaltonen LA, de la Chapelle A, Peltomaki P, Mecklin J-P, Jarvinen HJ. Cancer risk in mutation carriers of DNA-mismatch-repair genes. Int J Cancer 1999; 81:
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:
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:
Slide 62:
References 5

63. References
Solomon C, Burt RW Familial adenomatous polyposis. Last updated September 20, 2004, accessed July 22, 2005.
Predictive Cancer Genetics Steering Committee. Ontario physicians’ 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.
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:
Assessed on June 22, 2005.
Slide 63:
References 6

64. References
Johns LE, Houlston RS A systematic review and meta-analysis of familial colorectal cancer risk. Am J Gastroenterol. 2001; 96:
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.
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.
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:
Slide 64:
References 7

65. References
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; 331:
Yu H-JA, Lin KM, Ota DM, Lynch HT. Hereditary nonpolyposis colorectal cancer: preventive management. Cancer Treatment Rev 2003; 29:
Slide 65:
References 8

66. Slide 66:
The Genetics Education Project Logo

67. Extra Slides

68. 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.
For more information see:
Lu KH, Broaddus RR. Gynecologic cancers in Lynch syndrome/HNPCC. Fam Cancer 2005; 4:
Lu KH, Dinh M, Kohlmann W, Watson P, Green J, Syngal S, Bandipalliam P, Chen L-M, Allen B, Conrad P, Terdiman J, Sun C, Daniels M, Burke T, Gershenson DM, Lynch H, Lynch P, Broaddus RR. Gynecologic caner as a “sentinel cancer” for women with hereditary nonpolyposis colorectal cancer syndrome. Obstet Gynecol 2005; 105:
Rijcken FEM, Mourits MJE, Kleibeuker JH, Hollema H, van der Zee AGJ. Gynecologic screening in hereditary nonpolyposis colorectal cancer. Gynecol Oncol 2003; 91:74-80.
Brown GJE, St. John DJB, Macrae FA, Aittomaki K. Cancer risk in young women at risk of hereditary nonpolyposis colorectal cancer: implication for gynecologic surveillance. Gynecol Oncol 2001; 80:

69. 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
Tumour tissue with MSI variable repeat size 5 & 3
Normal tissue
2 repeats
MSI is a pathology finding specific
to HNPCC colon tumours

70. 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

71. 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:
Are deficient for immunohistochemical staining for the proteins
MSH2, MLH1 or MSH6 and/or
Show evidence of genetic instability of small repetitive DNA sequences (microsatellites) when compared to normal tissue.