Hereditary Colorectal Cancer

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 Rideout MS, CGC,
CCGC Certified Genetic Counsellor Project
Manager The Genetics Education Project Sean
Blaine BSc, MD, CCFP Mount Sinai Hospital,
University of Toronto Stratford,
Ontario Funded by Ontario Womens Health
Council Version January 2010
2
Acknowledgments

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

3
Outline

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

4
Cancer

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

5
Sporadic Cancer

• All cancer arises from changes in genes.
• But NOT all cancer is inherited
• Most CRC is sporadic 75 80
• Due to acquired mutations throughout a persons
  lifetime
• Causes unknown multifactorial
• Interaction of many factors age, environment,
  lifestyle, chance, unknown factors
• Sporadic cancer generally has a later onset

6
Clustering of Cancer in Families

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

7
Proportion of Hereditary CRC
Familial 15 Hereditary 5 Lynch syndrome
2-5 FAP lt1
Sporadic 80
8
Knudson two-hit Model Sporadic Cancer
ONE HIT (hitmutation)
Birth Two non-mutated copies of the gene
SECOND HIT
One mutation in one gene Second gene non-mutated
Two mutations - one in each gene
CANCER
9
Knudson two-hit Model Hereditary Cancer
ONE HIT (hitmutation)
SECOND HIT
Birth One mutation in one gene Second gene
non-mutated
Two mutations - one in each gene
CANCER
10
Compared to sporadic cancer people with
hereditary cancer have

• A higher risk of developing cancer
• A younger age of onset of cancer
• Generally lt 50 years of age
• Multiple primary cancers
• Generally have a family history of cancer
• Hereditary cancer is less common in the general
  population than sporadic cancer

11
Inherited Colorectal Cancer

• Two common syndromes
• Lynch syndrome
• Also known as Hereditary Non Polyposis Colorectal
  Cancer or HNPCC
• 2 - 5 of colorectal cancer
• Prevalence of 1 in 200 - 2,000
• Familial Adenomatous Polyposis (FAP)
• lt1 of colorectal cancer
• Prevalence of 1 in 8,000 14,000
• Autosomal dominant inheritance
• Prevalence depends on population

12
Autosomal Dominant Inheritance

• Legend
• B CRC gene with mutation
• b normal CRC gene

CRC mutation
Unaffected
bb
Bb
bb
Bb
Bb
bb
Susceptible CRC gene
Population Risk
Population Risk
Susceptible CRC gene
13
Colorectal cancer genes
when mutated

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

14
Lynch syndrome (HNPCC)

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

15
Cancer Risk in Individuals with Lynch syndrome
(HNPCC) to Age 70 Compared to General Population
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 lt1 11-19 56 years
Ovary 1.5 9-12 42.5 years
Hepatobiliary tract lt1 2-7 54 years
Urinary tract lt1 4-5 55 years
Small Bowel lt1 1-4 49 years
Brain / CNS lt1 1-3 50 years
from http//www.genetests.org
16
Familial Adenomatous Polyposis

• Chromosome 5, APC gene
• High penetrance
• Characterized by
• Early onset
• gt100 adenomatous polyps
• Variant form
• Attenuated FAP may occur with gt10 but lt100
  polyps.

17
Consequences of FAP

• Colorectal adenomatous polyps begin to appear at
  an average age of 16 years (range 7-36 years)
• Average age at diagnosis 34-43 years, when gt95
  have polyps

Age Individuals with colon cancer
21 7
45 87
50 93
From http//www.genetests.org
18
Consequences of FAP

• 50-90 develop small bowel polyps
• lifetime risk of small bowel malignancy is 4-12
• 50 develop gastric polyps
• 10 gastric cancer
• 10 develop desmoid tumours

19
Red Flags for hereditary colorectal cancer
consider referral to genetics

• Multiple cases in family with Lynch
  syndrome/HNPCC spectrum of cancers with at least
  1 relative with CRC or endometrial CA
• CRC at lt45 years
• Multiple Lynch syndrome cancers in 1 family
  member
• Family member with FAP or gt10 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

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
gt1 FDR with CRC 4 16
1 FDR Dx lt45 yrs 4 15
1 FDR Dx CRC adenoma 2 8
From http//www.cancer.gov
21
Case

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

22
Case continued

• Fathers side of the family
• uncle - CA ureter age 72
• uncle - CA colon age 56
• aunt - double primary endometrial CA age 45,
  colon CA age 68
• 1 cousin - endometrial CA age 40
• 2 cousins - both have colon CA

23
Janes Family Pedigree
Accident
Stroke
Nat Causes
AW
Mary Dx 45 CA Endometrial Dx 68 CA Colon
Steve Dx 72 CA Kidney
Bob Dx 56 CA colon
Paula Dx 66 CA- Br
MI 72
AW
AW
AW
Kevin, 67 AW
Jeana Dx 40 Ca-Endometrial
Christa Dx 52 CA Colon
Linda Dx 38 CA - colon
AW
AW
Jane, 26
24
Jane was referred to genetics A genetics
consultation involves

• Detailed family history information
• Pedigree documentation
• Confirmation of cancer history pathology
  reports/death certificates
• Medical exposure history
• Empiric risk assessment
• Hereditary cancer / genetic risk assessment
• Psychological assessment

25
A genetics consultation involves

• Assessment of eligibility for genetic testing
• Availability of living affected relative to be
  tested first
• Discussion of risks, benefits limitations of
  test
• Testing and disclosure of genetic test results
• May be months before results are available
• Determining patients thoughts about colorectal
  cancer - motivations for testing
• Screening/management recommendations

26
Recommendations for Janes family

• Janes 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 Janes family declines genetic testing then
  family members should follow high risk screening
  recommendations for CRC.
• Colonoscopy q1-2 years consider referral to a
  GYN to discuss endometrial cancer screening

27
Results from Genetic Testing

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

28
Risks/Benefits/Limitations of genetic
testingPositive test result

• Potential Risks
• Adverse psychological reaction
• Family issues/distress
• Uncertainty -incomplete penetrance
• Insurance/job discrimination
• Confidentiality issues
• Intervention may carry risk

• Potential Benefits
• Clinical intervention may improve outcome
• Family members at risk can be identified
• Positive health behaviour can be reinforced
• Reduction of uncertainty

29
Risks/Benefits/Limitations of genetic testing?
True 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

30
Risks/Benefits/Limitations of genetic testing?
Uninformative test result

• Potential Risks
• Continue clinical inventions which may carry
  risks
• Complacent attitude to health
• Uncertainty
• Continued anxiety

• Potential Benefits
• Future research may clarify test results
• Importance of positive health behaviour can be
  reinforced
• Some relief

31
What is the benefit of genetic testing? Can
anything be done to change risk /outcome?

• Patients with Lynch syndrome/HNPCC
• Colonoscopy beginning age 20-25 or 10 years
  younger than youngest CRC or adenomatous polyp
  diagnosis, whichever comes first
• Subsequent colonoscopy every 1-2 years
• Category of evidence III, grade C

Vasen et al. J Med Genet. 2007 44353-362.
32
What is the benefit of genetic testing? Can
anything be done to change risk /outcome?

• Evidence for screening in Lynch syndrome/HNPCC
• Cohort study of CRC screening 15 yr F/U
• Subgroup of Lynch syndrome carriers
• CRC in 8/44 with colonoscopy q3 years vs. 19/46
  controls ( p0.02)
• RR of CRC 0.44 (95 CI 0.2-0.9)
• RR of death 0.35 (95 CI 0.1-0.99)
• 15 yr survival 92 vs. 74

Jarvinin et al Gastroenterology 2000
33
What is the benefit of genetic testing? Can
anything be done to change risk /outcome?

• Lynch syndrome/HNPCC gynecological cancers
• Little evidence re GYN cancer screening
• Educate re symptoms of endometrial ovarian
  cancer
• Beginning age 30-35 consider 1-2 years
• Gynecological examination
• Trans-vaginal ultrasound /- aspiration biopsy
• Category of evidence III, grade C
• CA125
• Consider prophylactic hysterectomy and bilateral
  salpingo-oophorectomy (BSO)
• Grade C

Vasen et al. J Med Genet. 2007 44353-362
34
Lynch syndrome - Evidence for screening for
endometrial cancer (EC)

• Finnish HNPCC registry chart review for 10
  years
• N175 EC screening N83 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
  (P0.4)
• Renkonen-Sinisalo Int J Cancer 2006120821-824

35
What is the benefit of genetic testing? Can
anything be done to change risk /outcome?

• Lynch syndrome evidence for risk reducing
  surgery
• Chart Review of HNPCC mutation positive women
• Hysterectomy N 61
• No cases of endometrial cancer
• No hysterectomy N 254
• 69 cases of endometrial cancer 33
• Plt0.001
• Bilateral salpingo-oophorectomy (BSO) N47
• No cases of ovarian cancer
• No BSO N223
• 12 cases of ovarian cancer 5.5
• P0.09
• No peritoneal cancers in the study period
• Schmeler et al. NEJM 2006354261-269.

36
What is the benefit of genetic testing? Can
anything be done to change risk /outcome?

• Lynch syndrome/HNPCC screening for other cancers
• ONLY if there is a family history of the type of
  cancer listed below - controversial
• Gastric cancer
• Gastroduodenoscopy q1-2 years beginning age 30
  35 years
• Urinary tract cancer
• Renal U/S urine cytology q1-2 years beginning
  age 30 to 35 years
• Other cancers
• Screen as per family history of skin, small
  bowel, pancreaticobiliary cancers

37
What is the benefit of genetic testing? Can
anything be done to change risk/outcome?

• Patients with FAP
• Sigmoidoscopy every 1-2 years beginning at age 10
  to 12
• subsequent colonoscopy every 1-2 years
• Colonoscopy once polyps are detected
• Colectomy
• Annual colonoscopy if colectomy is delayed more
  than 1 year after polyps emerge

38
Management of Mutation Carriers Consider

• Psychosocial support to assist with
• Adjusting to new information
• most adjust within 3-6 months
• subset remain psychologically distressed
• Making decisions regarding management
• Addressing family issues, self concept, body
  image
• Dealing with future concerns
• Referral to support groups

39
Management of Mutation Carriers Consider

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

40
Resources

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

41
Case Examples
42
Assessing the Risk for Hereditary CRC
Using the Canadian Cancer Society triage card
(below), what category of risk do the following
family histories fit into?
43
Case 1
Alz -75
Accident
Old Age-82
Aneurysm-65
?Chol
AW
Colon CA Dx 34
ID DM
?Chol
AW
A W
?Chol
AW
Asthma
AW
Your Patient
44
Case 1
45
Case 1

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

46
Case 2
Prostate Ca Dx 72
Kidney Ca Dx 65
Alz -75
Aneurysm-65
AW
Colon Ca Dx 50
IDDM
ID DM
?Chol
Colon Ca Dx 49
AW
Endometrial Ca Dx 33
AW
Asthma
AW
Your Patient
47
Case 2
48
Case 2

• Answer
• High risk for hereditary CRC
• 3 relatives on the same side of the family, at
  least 1 CRC and 2 with any combination of Lynch
  syndrome-associated cancer AND
• 1 is a 1st degree relative of the other 2 and
• 1 relative diagnosed lt50 and
• At least 2 successive generations (suggestive of
  Lynch syndrome)
• Management
• Offer referral to hereditary CRC/genetics clinic
• Colonoscopy q 1-2 years beginning age 20 or 10
  years younger than youngest CRC diagnosis
• Educate patient about symptoms of endometrial
  cancer

49
Case 3
Accident
Alz -75
Aneurysm-65
Colon Ca Dx 74
AW
?Chol
IDDM
ID DM
?Chol
AW
A W
AW
Asthma
AW
AW
Your Patient Crohns disease
50
Case 3
51
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.

52
Case 4
Colon Ca Dx 74
Accident
Alz -75
Aneurysm-65
AW
?Chol
IDDM
ID DM
?Chol
AW
A W
Colon CA Dx 52
AW
AW
Your Patient
Asthma
53
Case 4
54
Case 4
A Good evidence B Fair evidence I
Insufficient evidence

• 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

55
Case 5
Lung Ca Dx 74 NON-smoker
Accident
Alz -75
Aneurysm-65
Lung Ca Dx 43 Smoker
Chronic cough
AW
ID DM
Colon CA Dx 61
AW
Mesothelioma Dx 45 Smoker
Chronic cough
AW
Your Patient
AW
Asthma
56
Case 5
57
Case 5
A Good evidence B Fair evidence I
Insufficient evidence

• Answer
• Population risk for CRC
• Patients 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

58
Case 6
Lung Ca Dx 74 Smoker
Accident
Alz -75
Aneurysm-65
Colon Ca Dx 42 1000
polyps
AW
ID DM
AW
AW
AW
AW
AW
Your Patient
Colon CA Dx 32
AW
Asthma
59
Case 6
60
Case 6

• Answer
• High risk for hereditary CRC
• gt10 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

61
The Genetics Education Project Committee

• 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

• 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

62
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1. 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 3311047-1049.
2. Yu H-JA, Lin KM, Ota DM, Lynch HT. Hereditary
   nonpolyposis colorectal cancer preventive
   management. Cancer Treatment Rev 2003
   29461-470.
3. Renkonen-Sinisalo L, Butzow R,Leminen A,
   Lehtovirta P, Mecklin J-P, Jarvinen HJ.
   Surveillance for endometrial cancer in hereditary
   nonpolyposis colorectal cancer syndrome. Int. J.
   Cancer. 2006 821-824.
4. Schmeler KM, Lynch HT, Chen L-M, Munsell MF,
   Soliman PT, Clark MB, Daniels MS, White KG,
   Boyd-Rodgers SG, Conrad PG, Yang KY, Rubin MM,
   Sun CC, Slomovitz BM, Gershenson DM, Lu KH.
   Prophylactic surgery to reduce the risk of
   gynaecologic cancers in Lynch syndrome. NEJM
   2006345261-269.
5. Koornstra JJ, Mourits MJE, Sijmons RH, Leliveld
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Extra Slides
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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
• 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 Lynch
syndrome colon tumours
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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

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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
• Are deficient for immunohistochemical staining
  for the proteins
• MSH2, MLH1, MSH6 and/or PMS2
• Show evidence of genetic instability of small
  repetitive DNA sequences (microsatellites) when
  compared to normal tissue.