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Audit of Lynch
Syndrome (HNPCC)
Carriers
Northern Genetic Service
Alex Henderson
Consultant Clinical Geneticist
Lorraine Cowley
Principal Genetic Counsellor
Lynch Syndrome/HNPCC
Update of Genetics of Lynch
Syndrome/HNPCC
 Results of Northern Genetics Service audit
of screening in patients with known MMR
genetic abnormalities
 Further audit plans
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Lynch syndrome/HNPCC
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Lynch syndrome (Hereditary non-polyposis colorectal
cancer) is an autosomal dominant genetic condition
which has a high risk of colon cancer as well as other
cancers including:
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endometrium,
ovary, stomach,
small intestine,
hepatobiliary tract,
upper urinary tract,
brain, skin.
The increased risk for these cancers is due to inherited
mutations that impair DNA mismatch repair.
DNA mismatch repair
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DNA mismatch repair is a system for recognising
and repairing erroneous insertion, deletion and
mis-incorporation of bases that can arise during
DNA replication and recombination, as well as
repairing some forms of DNA damage.
Mutations in the DNA mismatch genes
(specifically the human homologues of the Mut
proteins) affect genomic stability which can
result in microsatellite instability (MI).
Microsatellite Instability
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Microsatellites are repeated sequences of DNA. These
repeated sequences are common, and normal.
Although the length of these microsatellites is highly
variable from person to person, each individual has
microsatellites of a set length.
In cells with mutations in DNA repair genes, some of
these sequences accumulate errors and become longer
or shorter. The appearance of abnormally long or short
microsatellites in an individual's DNA is referred to as
microsatellite instability.
MI is implicated in most human cancers. Specifically the
overwhelming majority of cancers in HNPCC are
attributed to mutations in MMR genes .
Cancer risks in Lynch Syndrome
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Individuals with HNPCC mutation have about an
80% lifetime risk for colon cancer.
Two-thirds of these cancers occur in the
proximal colon.
The mean age of colorectal cancer diagnosis is
44 for members of families that meet the
Amsterdam criteria.
Women with HNPCC have a 80% lifetime risk of
endometrial cancer. The average age of
diagnosis of endometrial cancer is about 46
years.
Amsterdam criteria
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The initial Amsterdam criteria were a series of clinical
criteria that were colloquially known as the ‘‘3-2-1’’ rule:
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At least 3 relatives with histologically confirmed colorectal
cancer, 1 of whom is a first degree relative of the other 2; familial
adenomatous polyposis should be excluded;
At least 2 successive generations involved;
At least 1 of the cancers diagnosed before age 50.
These criteria were expanded to include the associated
non-colorectal cancers:
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3 or more relatives with an HNPCC associated cancer;
2 or more successive generations affected;
1 or more relatives diagnosed before the age of 50 years;
1 should be a first-degree relative of the other two.
Bethesda Guidelines
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The Bethesda guidelines are an alternative method for
the identification of individuals who should receive
genetic testing for Lynch syndrome related tumors:
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Colorectal carcinoma (CRC) diagnosed in a patient who is less
than 50 years old;
Presence of synchronous or metachronous CRC or other Lynch
syndrome-associated tumors, regardless of age;
CRC with high microsatellite instability histology diagnosed in a
patient less than 60 years old;
CRC diagnosed in one or more first-degree relatives with a
Lynch syndrome-associated tumour, with one of the cancers
being diagnosed at less than 50 years of age;
CRC diagnosed in two or more first-degree or second-degree
relatives with Lynch syndrome-associated tumours, regardless of
age
Genes implicated in HNPCC
 Genes
 MLH1
 MSH2
 MSH6
 PMS2
 PMS1
 TGFBR2
 MLH3
Frequency
30%
60%
7-10%
<5%
case reports
case reports
disputed
Locus
3p21.3
2p22
2p16
7p22
2q31q33
3p22
14q24.3
Genetic testing in Lynch Syndrome
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Genetic testing for mutations in DNA mismatch repair
genes is expensive and time-consuming.
In general, we try to identify those families where we are
most likely to identify mutations:
1. The Amsterdam Criteria are useful, but do not identify up to 30%
of potential Lynch syndrome carriers.
2. Microsatellite instability can be assessed in tumour specimens;
when microsatellite instability is identified (or MSI-H) there is a
high likelihood for a Lynch syndrome diagnosis.
3. Immunohistochemistry testing also allows testing for expression
of DNA mismatch repair genes; by combining this with MSI, an
additional >30% of Lynch syndrome carriers who would have
been missed on MSI profiling alone are identified.
Sensitivity of Amsterdam and
Bethesda Criteria
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Not all families fulfilling the clinical criteria for Lynch
syndrome have an identifiable deleterious mutation in
the MMR genes.
Conversely, many families who do not fulfil the criteria
have been found to harbour MMR mutations.
A recent review of sensitivity and specificity suggest that
the revised Amsterdam criteria are met by 62%, 48%,
87% and 38% of families with mutations in MSH2,
MSH6, MLH1 and PMS2.
The Bethesda criteria had low sensitivity for identifying
MSH6 or PMS2 mutations.
Amsterdam and Bethesda criteria are inadequate for
identifying all mutations – particularly in MSH6/PMS2,
implying that MSH6 mutations may be more common
than currently assumed.
Clinical Management in Lynch
Syndrome
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Screening remains mainstay of management.
NGS guidelines are based on The British
Society of Gastroenterology and the Association
of Coloproctology for Great Britain and Ireland
update guidelines of 2010:
 18-24
monthly colonoscopy from 25 years; 2 yearly
OGD from 50 years to 75 in patients with family
history of gastric cancer.
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Aspirin Prevents Cancer in Lynch Syndrome
http://www.audiomedica.com/oncology/longerfollow-up-reveals-aspirin-prevents-cancer-inlynch-syndrome/
Audit - Introduction
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212 patients identified, 197 suitable for audit
Aim: To find out the referral and follow up pattern
of patients who have received a MMR gene
diagnosis through the Northern Genetic Service.
Practice compared to department standards:
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Yearly bowel screening
 Gynaecological advice over 35, discussion about
surgery if peri or post menopausal
 Opportunity to access genetics department
How many patients have been
referred for Bowel Surveillance?
Reason for no referral
Number of
Patients
Future Contact
5
No referral
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Declined (1)
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No record (2)
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No Colon (3)
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One off (3) (too old to
start regular screening)
9
Offered referral but no
response
3
What type of Gynaecological
Surveillance is offered?
What Genetic Follow up is
offered?
Conclusion
Bowel Surveillance
 Gynaecological Awareness
 Genetic Follow Up
 What Next?
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