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Transcript
GENETIC MANAGEMENT OF A FAMILY HISTORY OF COLORECTAL CANCER
EXCLUDING FAP
Full Title of Guideline:
Author (include email and role):
GUIDELINES FOR THE GENETIC MANAGEMENT OF
A FAMILY HISTORY OF COLORECTAL CANCER
EXCLUDING FAP
Dr Nora Shannon Consultant Clinical Geneticist
Division & Speciality:
Family Health
Clinical Genetics
Scope (Target audience, state if Trust
Clinical Genetics department
wide):
Review date (when this version goes out
November 2017
of date):
Explicit definition of patient group
to which it applies (e.g. inclusion and
exclusion criteria, diagnosis):
Changes from previous version (not
Patients affected with or have a family history of bowel
cancer. Please refer to guidelines for inclusion/ exclusion
criteria.
Previous version not on intranet
applicable if this is a new guideline, enter
below if extensive):
Summary of evidence base this
guideline has been created from:
Evidence number 5 : expert committee reports or
opinions and / or clinical experiences of respected
authorities
This guideline has been registered with the trust. However, clinical guidelines are
guidelines only. The interpretation and application of clinical guidelines will remain the
responsibility of the individual clinician. If in doubt contact a senior colleague or expert.
Caution is advised when using guidelines after the review date or outside of the Trust.
Page 1 of 15
GUIDELINES FOR THE GENETIC MANAGEMENT OF A FAMILY HISTORY OF
COLORECTAL CANCER EXCLUDING FAP
Aim
That individuals at an increased genetic risk of colorectal and related
cancers are offered appropriate evidence based care.
Objectives
1. To achieve a consensus across our region
2. To ensure equity of service provision across the region.
3. To enable regional audit of the service.
The population lifetime risk is around 1 in 16 in the UK. About 15-20% of new
patients with colorectal cancer will have a family history of other affected relatives.
About 1% of new cases of colorectal cancer will have FAP and 3-4% Lynch
syndrome. Families who may be at increased risk of developing colorectal cancer
and related cancers are identified on the basis of their family history of these
cancers. These guidelines are for the management of patients with a family history
of colorectal cancer who do not have FAP
These guidelines include:
A. Guidelines for referral of patients with a family history of colorectal cancer from
primary care to a family history clinic.
B. Guidelines for the management of individuals with a family history of colorectal
and related cancers
C. Guidelines for the use of tumour testing to assess risk
D. Guidelines for assessing the significance of colorectal adenomas
E. Heterozygote tumour risks in Lynch syndrome
F. Guidelines for genetic testing of families with colorectal cancer
G. Guidelines for genetic testing when there is a history of sebaceous neoplasm
Page 2 of 15
A. GUIDELINES FOR REFERRAL OF PATIENTS WITH A FAMILY HISTORY
OF COLORECTAL CANCER FROM PRIMARY CARE TO A FAMILY
HISTORY CLINIC
The family history of some patients may indicate that they are at increased risk of
developing colorectal or related cancers. It may be helpful to refer these patients
to a family history clinic to further assess their risk and for advice about appropriate
management. Most hospitals now run a family history clinic under the auspices of
the surgical unit or gastroenterology. Other cancers, which are important to include
in the assessment of family history include endometrial, ovarian, renal pelvis, and
ureteric or small bowel.
Affected relatives should be in a first degree kinship ie they are first degree
relatives of each other. At least one should be a first degree relative of the
consultand if the consultand is unaffected. First-degree relatives (fdr) are parents,
children, brothers or sisters.
1.
Patients who DO NOT require referral and are at low risk
1 relative
 1 fdr who developed colorectal cancer over the age of 50
2 relatives
 2 first degree relatives (fdr) with an average age of colorectal cancer of
greater than 70 (this includes where both parents are affected).
Patients with the following family histories of cancer are at increased risk
and require referral:
2. Refer to Local Screening Unit (Low-Moderate Risk):
1 relative
 1 first degree relative (fdr) who developed colorectal cancer under the age
of 50
2 relatives
 2 relatives in a first degree kinship or both parents with an average age of
colorectal cancer 60-70
3.
Refer to Local Screening Unit (High-Moderate risk)
2 relatives
 2 first degree relatives (fdr) on the same side of the family with colorectal
cancer under the age of 60

3 relatives
 3 or more close relatives on the same side of the family with colorectal,
endometrial, ovarian, small bowel, ureteric or renal pelvis cancer.
Page 3 of 15
B. GUIDELINES FOR THE MANAGEMENT OF INDIVIDUALS WITH A FAMILY
HISTORY OF COLORECTAL AND RELATED CANCERS
Screening recommendations for Low-moderate and High-moderate risk groups
assume that MSI/IHC where performed is negative.
Low Risk
This group of patients do not require surveillance
Low-Moderate risk
Individuals at low-moderate risk have a modest increase in their colorectal cancer risk
which equates to around a 1 in 12 life-time risk without screening. Current evidence
suggests the following screening:
1 relative
 1 fdr < 50: one colonoscopy at 55 or at first consultation, whichever is later.
2 relatives
 2 relatives in a first degree kinship with an average age 60-70: one
colonoscopy at 55 years or at first consultation, whichever is later.
High-Moderate risk
Individuals at high-moderate risk have an increase in their colorectal cancer risk which
equates to around a 1 in 6 life-time risk without screening. Current evidence suggests
the following screening:
2 relatives
 2 relatives in a first degree kinship with an average age under 60 years: 5
yearly colonoscopy 50-75 yrs
3 relatives
 3 relatives in a first degree kinship where no one affected is <50 years: 5 yearly
colonoscopy 50-75 years
High risk
Individuals at high risk meet the Amsterdam or modified Amsterdam criteria and benefit
from colonoscopy. Although colonoscopy has been shown to reduce colorectal cancer
rate in patients with proven Lynch syndrome mutations and appears to be costeffective, surveillance of other organ systems has not yet been proven to be beneficial.
Modified Amsterdam criteria
 3 or more close relatives on the same side of the family with colorectal,
endometrial, small bowel, renal pelvic or ureteric cancer. At least two successive
generations are affected and one affected patient has had a cancer diagnosed at
less than age 50.
Page 4 of 15
The extracolonic cancers were chosen to provide a high mutation detection rate.
The inclusion or exclusion of stomach cancer was debated and was not included in
the final criteria. Hepatobilliary and brain (glioblastoma) were also excluded
although these form part of the Bethesda criteria and therefore will often trigger
MSI/IHC testing in the department.
Screening for families with a mutation in a MMR gene or positive MSI/IHC
(negative BRAF) suggestive of Lynch syndrome (affected and at 50% risk)
Bowel: 18 monthly -2 yearly colonoscopy from 25 years for life. Screening age may
be brought down if there has been a particularly young bowel cancer in a family
Endometrium and ovary: Surveillance as recommended by local Gynaecologist
from 35 years
Some evidence that total abdominal hysterectomy with
bilateral oopherectomy when childbearing is complete
may improve outcome but balance of risks and benefits
too close to justify a general recommendation and
colonoscopy may subsequently become difficult
Other:
Gastric cancer – there is no established benefit to regular endoscopies and the risk
is felt to be relatively low at 5%. The Mallorca group recommends screening for
H.Pylori infection and eradication if found.
Small bowel – currently the Mallorca group do not recommend surveillance.
Urinary tract – the Mallorca group do not recommend surveillance. Studies have
found the sensitivity of urine cytology to be low.
Breast cancer – some studies have reported an increased risk of developing breast
cancer which may or may not be confined to MLH1 carriers. At present women are
recommended to take up the National Breast Screening Programme.
Skin – there is no evidence base for screening for sebaceous adenomas or
carcinomas. If there is a clinical evidence of these lesions, a family history or a
mutation in MSH2 referral to a dermatologist for a one off assessment and advice
can be considered.
Page 5 of 15
Screening for families who fulfil the Modified Amsterdam criteria but are
MSI/IHC/MMR gene negative
Testing for other genes associated with bowel cancer should be considered
depending on the histology and number of polyps in family members eg FAP,
MYH. See guidelines for FAP for more details about these conditions.
Screening should be reduced to 5 yearly if MSI/IHC is negative. Screening is
usually offered from 35-75 unless there has been a younger cancer in the family
when colonoscopies should start 5 years before the age of the youngest affected in
the family. Screening for other cancers is not recommended if MSI/IHC is negative.
Screening for families who are Amsterdam negative but MSI high (BRAF
negative) and mutation has not been identified
3 yearly colonoscopy from 35 years for those affected and first degree relatives. If
there is an endometrial cancer or loss of MSH6 on IHC discuss the pros and cons
of referral to a gynaecologist if you have not been able to pursue genetic testing on
lymphocyte DNA.
Cases which are MSI high but where no mutation has been identified should be
discussed with a consultant to consider alternative explanations. See section
below about possibilities to consider where MSI is high but mutation testing is
negative.
Families where there are polyps
In most cases the screening offered will be on the basis of the family history of
cancer. Individuals who have polyps identified will have a repeat colonoscopy
based on the number of polyps and their histology as per the guidelines published
in Gut in 2010 by Cairns et al.
Where individuals have more than 10 adenomas identified, they will meet the
diagnostic criteria for attenuated FAP and should be screened as such. They will
qualify for additional genetic testing as per the flow chart.
Page 6 of 15
C. GUIDELINES FOR THE USE OF TUMOUR TESTING TO ASSESS RISK
The DNA mismatch repair complex functions as a spell-check system to repair
errors occurring when DNA is replicated during cell division. In tumours that
develop due to defective DNA mismatch repair, repetitive DNA sequences known
as microsatellites have a tendency to undergo a high level of genetic alteration.
High amounts of microsatellite instability (MSI) are found in nearly all the tumours
that arise in individuals with Lynch syndrome and 15% of non-Lynch syndrome
tumours. These latter tumours manifest either methylation of the MLH1 promoter or
acquired mutation in the BRAF gene, which is absent in Lynch syndrome tumours.
Immunohistochemisty (IHC) for MLH1, MSH2 and MSH6 allows targeted mutation
analysis for the appropriate Lynch syndrome gene so these techniques are
complimentary and help improve identification of families with an Lynch syndrome
mutation.
Strategies based on identification of patients suitable for tumour testing using the
revised Bethesda guidelines have shown if MSI and loss of protein expression are
identified, the postive predictive value of these results for an Lynch syndrome
tumour is 29%, the negative predictive value if 99% and the overall accuracy is
98% compared to an overall accuracy of mutation prediction of 70% based on
clinical criteria alone.
Use of tumour testing is important as a recent study has clearly shown that in
families who fulfil the Amsterdam criteria in whom MSI is not identified and IHC is
normal, the mean age of diagnosis of colorectal cancer is older than in the patients
with Lynch syndrome and the other tumours related to Lynch syndrome do not
appear to occur and therefore surveillance for these tumours is not indicated. It has
been suggested in this group of patients colonoscopy could start at a later age and
would only be required 5 yearly.
Tumour testing
MSI should be offered to all families who fulfil the Revised Bethesda criteria or
where there are two cases of CRC between 50-60 in a first degree kinship.
Abnormal or inconclusive results are followed by IHC. Endometrial cancers are
less likely to exhibit MSI and so if this is the only choice of tumour, IHC should also
be requested. Dysplastic polyps are less likely to show MSI and tissue showing
malignancy should be used when possible. Only polyps showing severe dysplasia
should be analysed.
If tumour tissue is not available, families who fulfil the modified Amsterdam criteria
and in whom there is an affected relative from whom a DNA sample can be
acquired, should be offered Lynch syndrome mutation analysis.
MSI results can be used to determine screening intervals but normal MSI in tissues
other than bowel tumours should be interpreted with caution and discussed with a
consultant before decisions about screening intervals are made.
Page 7 of 15
Abnormal tumour testing but normal mutation analysis
Where MSI on tumour tissue is high and IHC shows abnormalities alternative
explanations should be considered if mutation analysis is normal. Mutation
analysis should be guided by IHC results. Cases should be discussed with a
Consultant.
EPCAM gene deletions account for 1-3% of all Lynch syndrome cases and lead to
a high risk of bowel cancer (75% to the age of 70 years) and a low risk of
endometrial cancer (12% to 70 years). Tumours are MSI high with loss of MSH2
and MSH6. The MLPA kit used in the lab for the last 3 years will detect these but
review of testing should be considered in families who were tested before this.
In tumours with high MSI and loss of MSH2 some individuals will have a 10Mb
inversion on chromosome 2 (p21.1;22.2). This may be missed on routine
cytogenetic analysis but should be detected if the laboratory are directed.
Tumours which are MSI high and show loss of MLH1 and PMS2 have been seen
with germline hypermethylation of the MLH1 promoter but this is an extremely rare
mechanism. Testing can be requested via Northwick Park.
Page 8 of 15
Revised Bethesda Criteria
One affected individual:
1. Colorectal cancer diagnosed in a patient less than 50 years
or
2. Two or more colorectal cancers in the same individual, or colorectal cancer
and another tumour associated with Lynch syndrome* in the same individual,
regardless of the age that each tumour was diagnosed.
or
3. Colorectal cancer in a patient under 60 years of age, with histology suggestive
of MSI-H (tumor-infiltrating lymphocytes, Crohn’s-like lymphocytic reaction,
mucinous /signet-ring differentiation, or medullary growth pattern)
Two affected individuals:
4. One individual with colorectal cancer, plus a first degree relative  with
colorectal cancer or Lynch syndrome-related tumour*, with one of the cancers
diagnosed under age 50.
Three affected individuals:
5. One individual with colorectal cancer, plus two first or second degree relatives 
with colorectal cancer or Lynch syndrome-related tumours* at any age.
Additional referral criteria for Clinical Genetics/MSI:
6. Two relatives in a first degree kinship with bowel cancer at average age of 5060 years
*Endometrial, ovarian, renal pelvis/ureter, gastric, small bowel, biliary tract, brain (usually
glioblastoma as seen in Turcot syndrome), or sebaceous gland adenomas and keratoacanthomas
in Muir–Torre syndrome.

First-degree relatives (fdr) are parents, children brothers or sisters. Second degree relatives (sdr)
include grandparents, grandchildren, aunts, uncles, nieces or nephews. Affected relatives should
all be on the same side of the family, first degree relatives of each other and at least one should be
a first degree relative of the individual being referred.
Page 9 of 15
Algorithm for Laboratory Testing in Lynch syndrome (Lynch syndrome)
Page 10 of 15
D. GUIDELINES FOR ASSESSING THE SIGNIFICANCE OF COLORECTAL
ADENOMAS
No
No
Does the patient meet the criteria for the in-house polyp panel?



Yes
CRC and ≥3 adenomatous polyps
≥5 adenomatous polyps <60 yrs
≥10 adenomatous polyps ≥60yrs
In-house polyp
panel including
APC and MUTYH
+ve
-ve
Manage as
per
guideline
Does patient meet the criteria for Lynch syndrome testing?
No


Yes
Bethesda criteria or
2 relatives in a first degree kinship
with bowel cancer at average age
50-60 yrs
Test as per
protocol
-ve
+ve
Manage as
per guideline
Page
11 of 15testing for mixed polyposis or hyperplastic polyposis if
Consider
diagnostic criteria fulfilled*
* serrated polyposis syndrome - at least 5 serrated polyps proximal to the sigmoid
colon, 2 of which are greater than 10 mm in diameter; (2) any number of serrated
polyps occurring proximal to the sigmoid colon in an individual who has a firstdegree relative with serrated polyposis; and (3) more than 20 serrated polyps of
any size distributed throughout the colon
E. HETEROZYGOTE TUMOUR RISKS IN Lynch syndrome
Tumours from the majority of Amsterdam criteria positive families are MSI
postive. If mutation analysis is performed in MLH1, MSH2, PMS1 and PMS2
approximately 70% of patients will have a mutation. In CRC families who do not
fulfil the Amsterdam criteria, 8-30% with have an MLH1 or MSH2 mutation.
Cancer type
Colon
Endometrium
Stomach
Ovary
Hepatobiliary tract
Urinary tract
Small bowel
Brain/central
nervous system
Sebaceous
neoplasms
General Population
risk
5.5%
2.7%
<1%
1.6%
<1%
<1%
<1%
<1%
Life time risk
Mean age of onset
52-82%
25-60%
6-13%
4-12%
1.4-4%
1-4%
3-6%
1-3%
44-61 years
48-62 years
56 years
42.5 years
Not reported
55 years
49 years
50 years
<1%
1-9%
Not reported
Aamio et al (1999), Vasen et al (2001), American Cancer Society (2002), Hampel et al (2005),
Ponti et al (2006), South et al (2008), Watson et al (2008), Barrow et al (2009), Stoffel et al (2009)
MLH1
MSH2
MSH6
35-65%
35-75%
Endometrial cancer 20-25%
(women only)
Ovarian cancer
(women only)
Bowel cancer
10-15%
EPCAM
Population
Risk
20-70% (men)
15-20%
10-30% (women)
75%
6%
30-40%
25-70%
15%
15%
2%
10%
Similar to
population
Similar to
population
10%
1-2%
From Royal Marsden guidelines
Page 12 of 15
PMS2
Genotype/Phenotype Correlation
Evidence is accumulating that the tumour risk for MLH1 and MSH2 may differ
(Vasen et al (1996) Gastroenterology; 110: 1020-1027,Lin et al (1998) J Gastrointest Surg; 2: 6771, Vasen et al (2001) J Clin Oncol; 19: 4074-4080, Parc et al (2003) J Med Genet; 40:208-213).
The lifetime risk of developing cancer at any site appears higher with MSH2
mutations. The risk of developing colorectal and endometrial cancer is increased
in MSH2 heterozygotes compared to MLH1 heterozygotes. MSH2 heterozygotes
have a significantly greater risk of developing urinary tract tumours (12%)
compared to MLH1 heterozygotes (1.3%). In MSH6, the lifetime risk of CRC is
44% for men and 20% for women and 44% risk for endometrial cancer. It has
been suggested that colonoscopy may be commenced from 30 in individuals
from MSH6 families. In this region we have elected to keep bowel screening the
same for all Lynch syndrome genes starting at 25 years.
Metachronous Tumours
Approximately 90% lifetime risk of a second colonic malignancy after one tumour
resection (25% at 14 years, 50% at 20 years)
Approximately 80% lifetime risk of developing a colonic cancer after an
endometrial cancer
(Parc et al (2003) J Med Genet; 40:208-213)
F. GUIDELINES FOR GENETIC TESTING OF FAMILIES WITH COLORECTAL
AND RELATED CANCERS.
Patients with colorectal cancer who fall into the high-risk group who fulfil the
Amsterdam criteria can be offered genetic testing in order to try and identify a
mutation in one of the Lynch syndrome genes. Patients who undergo genetic
testing must:
1) Be referred to the Clinical Genetics department
2) Receive genetic counselling about the implications of a positive result
3) Give informed, written consent for the test.
4) If terminally ill, blood can be taken by the referring physician for DNA storage
and genetic counselling and discussion of testing can be performed at a later
stage but the patient must identify a family member to whom the result can be
given
Criteria for a diagnostic genetic test
1) Individual has either colorectal or related cancer.
2) Individual comes from a high risk family that fulfils the modified Amsterdam
Criteria. Every effort should be made to confirm the diagnoses using the
available resources including hospital and GP notes and the cancer registry.
3) Tumour testing will be performed on patients fulfilling the Bethesda criteria or
with 2 CRCs between 50-60 in a first degree kinship where samples are
available. A subset of patients fulfilling the Bethesda criteria will go forward for
Lynch syndrome molecular testing
Once a mutation has been identified in an individual a predictive genetic test can
be offered to unaffected at-risk individuals within the family.
Page 13 of 15
Criteria for a predictive genetic test
1) Individual should be over 16 but in practice it is rare for testing to be requested
below 18 years.
2) They should receive genetic counselling prior to the blood being taken which
should include
 screening options
 discussion of prophylactic hysterectomy and oopherectomy in women who
have completed their families
 insurance issues
G. GUIDELINES FOR GENETIC TESTING WHEN THERE IS A HISTORY OF
SEBACEOUS NEOPLASM
For individuals referred with a sebaceous neoplasm the Mayo Muir-Torre
syndrome risk score algorithm below should be used. Abnormal IHC on a
sebaceous neoplasm is a poor predictor of Lynch syndrome.
Those with a score of ≥ 2 should be offered molecular genetic testing.
Variable
Age at sebaceous neoplasm diagnosis
60 or older
Younger than 60
Total number of sebaceous neoplasms
1
2 or more
Personal history of any Lynch related
cancer
No
Score
0
1
0
2
0
Yes
1
Family history of any Lynch related
cancer
No
0
Yes
1
Page 14 of 15
References
1. Guidance on Commissioning Cancer Services.
2. Cole TRP & Sleightholme HV (2000) BMJ; 301:366-368
3. Vasen HFA, et al (1998) Cancer; 82(9); 1632-1637
4. Jarvinen HK et al (1995). Gastroenterology; 108:1405-1411
5. Burke et al (1997) JAMA; 277 (11); 915-919
6. Cannon-Albright LA et al (1994) American Journal of Gastroenterology; 89(6):
827-831
7. Lindor et al (2006) JAMA; 296 :1507-1517
8. Pinol et al (2005) JAMA; 293:1986-1994
9. Hendriks et al (2004) Gastroenterology; 127:17-25
10. Lindor et al (2005) JAMA; 293:1979-1985
11. Watson et al (2008) Int J Cancer;123(2):444-449
12. GeneClinics : Lynch syndrome 2011
13. Cairns et al (2010)Gut ;59 :666-689
14. Kempers et al (2011) Lancet Oncol ;12 :49-55
Author:
Dr N L Shannon, Clinical Genetics Service 6/11/15
Review Date:
November 2017
Version 2
Page 15 of 15