Transcript No Slide Title

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 Women’s Health Council
Version: January 2010
Acknowledgments

Reviewers: Members of The Genetics Education Project
(see slide 51)
+ Kara M. Semotiuk, MS, (C)CGC Genetic Counsellor
Heidi Rothenmund, MS, (C)CGC Genetic Counsellor
Familial GI Cancer Registry, Mount Sinai Hospital

Funded by:
Ontario Women’s Health Council
as part of its funding to
The Genetics Education Project
* Health care providers must use their own clinical judgment in addition to the information
presented herein. The authors assume no responsibility or liability resulting from the
use of information in this presentation.
Outline
Sporadic verses familial cancer
 Hereditary colorectal cancer syndromes
 Referral guidelines
 Benefits, risks and limitations of genetic
testing
 Management
 Case examples

Cancer
All cancer involves changes in genes….
Threshold effect:
 During mitosis & DNA replication
 mutations
occur in the cell’s genetic code
Mutations are normally corrected by DNA
repair mechanisms
 If repair mechanism or cell cycle regulation is
damaged

 Cell


accumulates too many mutations
reaches ‘threshold’
tumour development
Sporadic Cancer

All cancer arises from changes in
genes….
 But
NOT all cancer is inherited
 Most CRC is sporadic ~75 – 80%

Due to acquired mutations throughout a person’s
lifetime:
Causes unknown – multifactorial
 Interaction of many factors: age, environment, lifestyle,
chance, unknown factors


Sporadic cancer generally has a later onset
Clustering of Cancer in Families

~6% lifetime risk of CRC in general population
~20% of people with CRC have a family history:

~15% of CRC is familial:




Environmental factors
Chance
Undiscovered gene mutation
 Generally

not eligible for genetic testing
~5% of CRC cancer is hereditary

Caused by an inherited gene mutation that puts them at
increased risk for cancer


Majority is Lynch syndrome/HNPCC (Hereditary Non-Polyposis
Colorectal Cancer)
Small fraction is Familial Adenomatous Polyposis (FAP) or other
rare cancer syndromes
 May
be eligible for genetic testing
Proportion of Hereditary CRC
Familial ~15%
Hereditary ~5%
Lynch syndrome ~ 2-5%
FAP ~ <1%
Sporadic 80%
Knudson ‘two-hit’ Model
Sporadic Cancer
ONE HIT
(hit=mutation)
Birth: Two non-mutated
copies of the gene
SECOND
HIT
One mutation in one gene;
Second gene non-mutated
CANCER
Two mutations - one in
each gene
Knudson ‘two-hit’ Model
Hereditary Cancer
ONE HIT
(hit=mutation)
SECOND
HIT
Birth: One mutation in one
gene; Second gene nonmutated
CANCER
Two mutations - one in
each gene
Compared to sporadic cancer people
with hereditary cancer have…
A higher risk of developing cancer
 A younger age of onset of cancer

 Generally
< 50 years of age
Multiple primary cancers
 Generally have a family history of cancer
Hereditary cancer is less common in the
general population than sporadic cancer

Inherited Colorectal 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)
 <1%
of colorectal cancer
 Prevalence of 1 in 8,000 – 14,000*

Autosomal dominant inheritance
*Prevalence depends on population
Autosomal Dominant Inheritance
Legend
CRC mutation
Unaffected
Bb
bb
Bb
Susceptible
CRC gene
B: CRC gene
with mutation
b: normal
CRC gene
bb
Population
Risk
Bb
Susceptible
CRC gene
bb
Population
Risk
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.
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
Cancer Risk in Individuals with Lynch syndrome
(HNPCC) to Age 70 Compared to General
Population
Cancer
General
Population Risk
Lynch syn.
Risk
Mean Age of
Onset in Lynch
Colon
7%
80%
45 years
Endometrium
2.7%
20-60%
46 years
Stomach
<1%
11-19%
56 years
Ovary
1.5%
9-12%
42.5 years
Hepatobiliary
tract
<1%
2-7%
54 years
Urinary tract
<1%
4-5%
~55 years
Small Bowel
<1%
1-4%
49 years
Brain / CNS
<1%
1-3%
50 years
from: http://www.genetests.org
Familial Adenomatous Polyposis
Chromosome 5, APC gene
 High penetrance
 Characterized by:

 Early
onset
 >100 adenomatous polyps
 Variant form:
 Attenuated FAP may occur with >10 but
<100 polyps.
Consequences of FAP


Colorectal adenomatous polyps begin to appear
at an average age of 16 years (range 7-36
years)
Average age at diagnosis: 34-43 years, when
>95% have polyps
Age Individuals with colon
cancer
21
7%
45
87%
50
93%
From: http://www.genetests.org
Consequences of FAP
 ~50-90%
lifetime
develop small bowel polyps
risk of small bowel malignancy is
4-12%
 ~50%
develop gastric polyps
~10%
 ~10%
gastric cancer
develop desmoid tumours
Red Flags for hereditary colorectal cancer
– consider referral to genetics






Multiple cases in family with Lynch syndrome/HNPCC
spectrum of cancers with at least 1 relative with CRC
or endometrial CA
CRC at <45 years
Multiple Lynch syndrome cancers in 1 family member
Family member with FAP or >10 adenomatous polyps
Family member with known mutation
Family member with colonic adenoma or cancer with
high microsatellite instability (MSI)


See extra slides following references for more information
about MSI
Not all who are referred will have genetic testing
Risk of Developing Colorectal Cancer
Family History
Relative Risk
for CRC
Absolute Risk of
CRC by age 79
No family history
1
4%
1 FDR with CRC
2
9%
>1 FDR with CRC
4
16%
1 FDR Dx <45 yrs
4
15%
1 FDR Dx CRC
adenoma
2
8%
From: http://www.cancer.gov
Case
 Jane
- healthy 26 y.o.
 Office visit for a routine pap smear
and renewal of birth control pills
 History:
Any
cancer in the family?
 Mother with breast cancer at 66
Case continued…
 Father’s
uncle
side of the family:
- 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
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
Jane was referred to genetics…
A genetics consultation involves:


Detailed family history information
Pedigree documentation
 Confirmation
of cancer history: pathology
reports/death certificates




Medical & exposure history
Empiric risk assessment
Hereditary cancer / genetic risk assessment
Psychological assessment
…A genetics consultation involves:

Assessment of eligibility for genetic testing
 Availability
of living affected relative to be tested first

Discussion of risks, benefits & limitations of test

Testing and disclosure of genetic test results
 May


be months before results are available
Determining patient’s thoughts about colorectal
cancer - motivations for testing
Screening/management recommendations
Recommendations for Jane’s family

Jane’s paternal family history is suggestive of Lynch
syndrome/HNPCC.

Jane was asked to discuss genetic testing with her
family members diagnosed with cancer.

Appropriate to test an affected member first.

If a mutation found in one of the Lynch syndrome genes
then sequential testing of the family can be performed.

If Jane’s family declines genetic testing then family
members should follow high risk screening
recommendations for CRC.
Colonoscopy q1-2 years; consider referral to a GYN to
discuss endometrial cancer screening

Results from Genetic Testing

Positive
 Deleterious

mutation identified
Negative
 Interpretation
differs if a mutation has previously been
identified in the family



Mutation known – true negative
Mutation unknown – uninformative
Variant of unknown significance
 Significance
will depend on how variant tracks
through family, i.e. is variant present in people with
disease?
 Can use software to predict functional significance
 Check with lab: ? reported previously
Risks/Benefits/Limitations
of genetic 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
Risks/Benefits/Limitations
of genetic testing?
True Negative test result
Potential Benefits:
 Avoidance of
unnecessary clinical
interventions
 Emotional - relief
 Children can be
reassured
Potential Risks:
 Adverse
psychological reaction
(i.e. survivor guilt)
 Dysfunctional family
dynamics
 Complacent attitude
to health
Risks/Benefits/Limitations
of genetic testing?
Uninformative test result
Potential Risks:
Potential Benefits:
 Continue clinical
 Future research may
inventions which may
clarify test results
carry risks
 Importance of positive
 Complacent attitude to
health behaviour can
health
be reinforced
 Uncertainty
 Some relief
 Continued anxiety
What is the benefit of genetic testing?
Can anything be done to change risk /outcome?

Patients with Lynch syndrome/HNPCC:
 Colonoscopy
beginning age 20-25 or 10 years
younger than youngest CRC or adenomatous
polyp diagnosis, whichever comes first
 Subsequent

colonoscopy every 1-2 years
Category of evidence III, grade C
Vasen et al. J Med Genet. 2007; 44:353-362.
What is the benefit of genetic testing?
Can anything be done to change risk /outcome?

Evidence for screening in Lynch
syndrome/HNPCC:
Cohort study of CRC screening – 15 yr F/U
 Subgroup of Lynch syndrome carriers
 CRC in 8/44 with colonoscopy q3 years vs. 19/46
controls ( p=0.02)
 RR of CRC = 0.44 (95% CI 0.2-0.9)
 RR of death = 0.35 (95% CI 0.1-0.99)
 15 yr survival 92% vs. 74%

Jarvinin et al Gastroenterology 2000
What is the benefit of genetic testing?
Can anything be done to change risk /outcome?

Lynch syndrome/HNPCC gynecological cancers:
 Little
evidence re GYN cancer screening
 Educate re symptoms of endometrial & ovarian cancer
 Beginning age 30-35 consider 1-2 years:


Gynecological examination
Trans-vaginal ultrasound +/- aspiration biopsy


Category of evidence III, grade C
CA125
 Consider
prophylactic hysterectomy and bilateral salpingooophorectomy (BSO)

Grade C
Vasen et al. J Med Genet. 2007; 44:353-362





Lynch syndrome - Evidence for screening
for endometrial cancer (EC):
Finnish HNPCC registry – chart review for 10 years
N=175 EC screening; N=83 no EC screening
Screening consisted of: GYN exam (100%), trans-vaginal
U/S (94%), endometrial biopsy (74%)
Median screening interval 3 years/ Median age 52 years
Screening group: 14 cases of EC detected





No screening group:




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
Number of EC cases not reported
6 EC deaths
Survival curves: 100% screening group; 92% no screening
Differences b/w survival curves not significant (P=0.4)
Renkonen-Sinisalo Int J Cancer 2006:120:821-824
What is the benefit of genetic testing?
Can anything be done to change risk /outcome?

Lynch syndrome – evidence for risk reducing surgery


Chart Review of HNPCC mutation positive women
Hysterectomy N = 61


No hysterectomy N = 254



No cases of ovarian cancer
No BSO N=223



69 cases of endometrial cancer – 33%
P<0.001
Bilateral salpingo-oophorectomy (BSO) N=47


No cases of endometrial cancer
12 cases of ovarian cancer – 5.5%
P=0.09
No peritoneal cancers in the study period
Schmeler et al. NEJM 2006;354261-269.
What is the benefit of genetic testing?
Can anything be done to change risk /outcome?


Lynch syndrome/HNPCC screening for other
cancers:
ONLY if there is a family history of the type of
cancer listed below - controversial
 Gastric cancer
 Gastroduodenoscopy q1-2 years beginning age 30 – 35
years
 Urinary tract cancer
 Renal U/S + urine cytology q1-2 years beginning age 30 to
35 years
 Other cancers
 Screen as per family history of skin, small bowel,
pancreaticobiliary cancers
What is the benefit of genetic testing?
Can anything be done to change risk/outcome?
 Patients
with FAP:
Sigmoidoscopy
every 1-2 years
beginning at age 10 to 12
 subsequent
colonoscopy every 1-2 years
Colonoscopy
once polyps are detected
Colectomy
Annual
colonoscopy if colectomy is
delayed more than 1 year after polyps
emerge
Management of Mutation Carriers
Consider…
 Psychosocial support to assist with:
 Adjusting
to new information
most adjust within 3-6 months
 subset remain psychologically distressed

 Making
decisions regarding management
 Addressing family issues, self concept, body
image
 Dealing with future concerns

Referral to support groups
Management of Mutation Carriers
Consider…

Additional psychosocial support may be needed
for high risk individuals such as those with:
 History
 Poor
of depression/anxiety
coping skills
 Inadequate
 Multiple
 Loss
social support / conflict in the family
losses in the family
of parent at a young age
 Recent
 Multiple
loss
surgical procedures
Resources

The National Cancer Institute:
 http://www.cancer.gov/
Gene Tests: http://www.genetests.org
 Colon Cancer Alliance:

 http://www.ccalliance.org/
Canadian Cancer Society: www.cancer.ca
 Cancer Genetics Support Group of
Canada (CHGSGC):

Contact Name: Nancy Schofield, President
16 Redford Road Canada
London, ON N5X 3V5
Email: [email protected]
Case
Examples
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?
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
Case 1
Legend
Colon
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
Case 2
Legend
Colon
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
Case 2
Legend
Colon
Endometrial
Kidney
Prostate
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
is a 1st degree relative of the other 2 and
 1 relative diagnosed <50 and
 At least 2 successive generations (suggestive of Lynch
syndrome)
1

Management:
 Offer
referral to hereditary CRC/genetics clinic
 Colonoscopy q 1-2 years beginning age 20 or 10 years
younger than youngest CRC diagnosis
 Educate patient about symptoms of endometrial cancer
Case 3
Legend
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
Case 3
Legend
Colon
Crohn’s
disease
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.
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
Case 4
Legend
Colon
Case 4
Answer:




A = Good evidence
B = Fair evidence
I = Insufficient evidence
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
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
Case 5
Legend
Colon
Lung
Case 5
Answer:


A = Good evidence
B = Fair evidence
I = Insufficient evidence
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
Case 6
Legend
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
~1000
polyps
Asthma
A&W
Alz -75
ID DM
Colon CA Dx 32
Case 6
Legend
Colon CA
Lung CA
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
The Genetics Education Project Committee








June C Carroll MD CCFP
Judith Allanson MD
FRCP FRCP(C) FCCMG
FABMG
Sean Blaine MD CCFP
Mary Jane Esplen PhD
RN
Sandra Farrell MD
FRCPC FCCMG
Judy Fiddes
Gail Graham MD FRCPC
FCCMG
Jennifer MacKenzie MD
FRCPC FAAP FCCMG







Wendy Meschino MD
FRCPC FCCMG
Joanne Miyazaki
Andrea L. Rideout MS
CGC CCGC
Cheryl Shuman MS CGC
Anne Summers MD
FCCMG FRCPC
Sherry Taylor PhD
FCCMG
Brenda Wilson BSc MB
ChB MSc MRCP(UK)
FFPH
References
1.
Offit K Clinical Cancer Genetics: Risk Counseling and
Management. Wiley-Liss, New York. 1998.
2.
Statistics from the Canadian Cancer Society:
http://www.ontario.cancer.ca/ccs/internet/standard/0,3182,3543_1
4447_371429_langId-en,00.html accessed on June 22, 2005.
3.
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: 1851-1860.
4.
Mitchell RJ, Farrington SM, Dunlop MG, Campbell H. Mismatch
repair genes hMLH1 and hMSH2 and colorectal cancer: a huge
review. Am J Epidemiol 2002; 156:885-902.
References
5.
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; 71:3493-3501.
6.
Lightning bolt photo credit:
http://www.ghouli.com/articles/sp/mainstream_4b.htm
7.
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: 1643-1645.
8.
American Gastroenterological Association (The Clinical Practice
and Practice Review Committee). AGA technical review on
hereditary colorectal cancer and genetic testing. Gastroenterology
2001;121:198-213.
References
9.
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. Populationbased molecular detection of hereditary nonpolyposis colorectal cancer. J
Clin Oncol 2000;18: 2193-2200.
10.
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; 339:511-518.
11.
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
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Extra Slides
What is Microsatellite Instability (MSI)?
Microsatellites are repetitive
segments of DNA
The same number of repeats are
present
in every cell
Normal microsatellite
with 2 repeats
Microsatellite Instability:
The number of microsatellite repeats
differs between normal cells/tissue
Normal tissue
and tumour cells/tissue
MSI is a pathology finding specific
to Lynch syndrome colon tumours
2 repeats
Tumour tissue
with MSI variable
repeat size 5 & 3
Pathology & Genetic Evidence for
Increased Risk of Hereditary CRC






Principle: Mutations of the genes MSH2, MLH1, MSH6 and PMS2
increase the rate of genetic mutation in human cells.
Small repetitive sequences (microsatellites) are very susceptible to
increases in the mutation rate.
These repetitive sequences can be surveyed to see if there are
differences in their sequence between the normal and tumor tissues
from an individual.
If changes are seen the tumor can be referred to as showing
“microsatellite instability”.
Typically there is good concordance between seeing that a tumor is
by immunohistochemistry immunodeficient for one of these gene
products and the finding of microsatellite instability.
Observing either one or both in a tumor increases the likelihood a
familial mutation is present
Pathology and Genetic Evidence for
Increased Risk of Hereditary Colorectal
Cancer


Colonic ademoma or other Lynch syndrome
associated cancers can be found in the
laboratory to have one or both of the following
properties which increase the likelihood a
familial mutation is responsible.
The tumors:
1.
Are deficient for immunohistochemical staining for
the proteins

2.
MSH2, MLH1, MSH6 and/or PMS2
Show evidence of genetic instability of small
repetitive DNA sequences (microsatellites) when
compared to normal tissue.