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4 Lynch Syndrome 81
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Fig. 4.2 Diagnostic pathway for colorectal cancer without known LS pathogenic variant. Following diagnosis of CRC MMR status is useful for deciding oncological treatment (adjuvant or
neoadjuvant), further testing if found to be dMMR can diagnose LS and ongoing surveillance and
secondary prevention as well as cascade testing to family members can commence. Created with
BioRender.com
Fig. 4.3 Diagnostic pathway for colorectal cancer with known LS pathogenic variant. If patient
has a known pathogenic LS variant and is diagnosed with cancer, they still must undergo MMR
testing on tumour but, surgical options including extended colectomy and risk reduction TAH BSO
can be considered. Created with BioRender.com
In LS there is monoallelic loss of a mismatch repair protein gene. Cancer
can develop when a somatic “second hit” occurs and there is inactivation of the
remaining functional MMR allele (Fig. 4.4). Because of this second hit, mismatch mutations can occur and accumulate which results in tumours that are
hypermutated [10] [More detail in Biology].
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Fig. 4.4 Demonstration of how Lynch-associated dMMR cancers develop compared to sporadic
dMMR cancers. Sporadic cancers need to undergo two mutations compared to Lynch cancers
where there is one mutation present in the germline which affects every cell [11]. Created with
BioRender.com
CMMRD
Congenital mismatch repair deficiency (CMMRD) is a rare condition when two
parents with LS have an offspring with biallelic loss of MMR genes [12]. It
causes early onset fatal cancer, most commonly brain tumours and haematological malignancies (T-lymphoblastic lymphomas) in the first decade of life. The
severity depends on which pathogenic variant is affected. Any patients surviving
into adulthood usually have PMS2 biallelic loss. Affected patients can develop
typical LS cancers but, usually in 2nd and 3rd decades of life.
Current European guidelines recommend (adults) [12, 13]:
1. Lower GI endoscopy 6 monthly
2. UGI capsule and endoscopy annually
3. MRI Brain and whole body annually
4. Consider at risk organs; urological, pancreatic.
This rare condition should be managed in specialist centres.
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4.2 History and Epidemiology
4.2.1 History of Lynch Syndrome
Family G, later identified to have LS, were identified in 1895 by Aldred Scott
Warthin [14, 15]. Pauline Gross, a seamstress reported family members across
generations developing endometrial and gastrointestinal tract cancers (Fig. 4.5).
Warthin noted the potential importance of family history of cancer when seen in
15% of the 1600 carcinomas coming through his laboratory.
Henry Lynch revisited “Family G” in the 1960s noting these individuals developed cancer (uterus, colon, stomach) at a younger age when compared to sporadic
cases. His thesis on “Familial Cancer Syndrome” in 1973 reviewed another family
which had more non-colonic cancers, therefore the terms; Lynch Syndrome I and
II. In 1985 Lynch named this syndrome ‘hereditary non-polyposis CRC’ (HNPCC)
due to the absence of a ‘polyposis’ phenotype.
As the molecular basis of CRC and pathways to carcinogenesis were understood in the laboratory in the 1980s, features differentiating familial and sporadic
cancers were noted, specifically “loss of heterozygosity” and changes in lengths of
microsatellites (now known to be features of microsatellite instability [MSI]) [16,
17]. These changes were only present in some cancers, but when present numbered
Fig. 4.5 The pedigree of Family G as described in the article in 1913; L—living, N—normal,
Op—operated, Carc—carcinoma [15]
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in the thousands [13, 18, 19]. By elucidating the link between DNA replication
‘mismatch’ errors, causing MSI, and the genes which repair these errors, MSH2
was the first to be recognised [20–27]. Subsequently, the genetic understanding
of the disease was discovered, and the term Lynch syndrome was applied, noting these families had constitutional pathogenic variants in DNA mismatch repair
genes; MLH1, MSH2, MSH6 and PMS2.
History of clinical prediction and testing
Prior to wide availability of tumour or genetic testing there were clinical criteria
to identify high risk families for further testing. These included the Amsterdam
Criteria [28] to identify high-risk families and Bethesda criteria [29] for highrisk cancer patients requiring testing for LS. These combined risk factors related
to personal, family history of colon and endometrial cancer with diagnostic age
limits and were used to identify higher risk and populations for further academic
categorisation and evaluation.
Sensitivity of these criteria to identify MLH1 and MSH2 pathogenic variants has
been studied. It was found that when reviewing 70 families with suspected hereditary CRC the sensitivity and specificity of the diagnostic criteria were variable.
Amsterdam criteria sensitivity 61% and specificity 67%, modified and Amsterdam
II criteria were more accurate with 72% sensitivity and 78% specificity [30]. The
Bethesda guidelines had a higher sensitivity 94% and lower specificity of 25%
but were designed to select CRC patients for further molecular testing in the era
before universal testing [30].
With universal testing we can recognise the gene and sex-specific differences
in clinical severity i.e., penetrance to understand different phenotypes. Given this
new pathway, clinical criteria are largely redundant, however, in lower resourced
health systems they could be employed.
Lynch syndrome and it’s ‘mimics’
If there is no confirmed pathogenic variant in MMR genes or EPCAM then there
are clinical and/or molecular presentations that largely represent ‘mimics’ rather
than true diagnoses of Lynch syndrome, outlined in Table 4.1 [31].
4.2.2 Epidemiology
The population prevalence of LS is estimated to be 1:400-450 or higher [1, 33,
34]. The UK Biobank study recruited 49,738 healthy patients aged 40–69 via
NHS register, finding 76 patients with a LS pathogenic variant (0.2%), 1 in~ 654
(MLH1 = 19, MSH2 = 6, MSH6 = 43, PMS2 = 8). Of these, 22.4% of carriers developed colorectal or endometrial cancer despite contemporary clinical care,
compared to 1.9% of the non-carriers [35] and 61.7% of LS pathogenic variant
carriers remained cancer free aged 75. However, there was a significant difference
in cumulative incidence of disease with a positive family history. Similarly, the
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Tab le 4.1 The spectrum of Lynch syndrome (LS) and LS-mimics
Ter m MMR
Lynch syndrome dMMR MMR germline pathogenic variant 3.5
dMMR CRC dMMR Mismatch repair deficient CRC, usually
dMMR CRC
Lynch syndrome
‘excluded’
Lynch-like
syndrome
HNPCC
Hereditary
non-polyposis
colon cancer
Familial Colon
Cancer
“Syndrome X”
Other Mendelian
syndrome
status
dMMR A diagnosis of LS is highly unlikely because an
dMMR Unexplained dMMR CRC, i.e., where somatic
dMMR/
pMMR
pMMR Patients who meet the Amsterdam Criteria for
dMMR/
pMMR
Definition Proportion
confirmed by tumour testing with either IHC or
MSI, but where germline testing may or may
not confirm a LS diagnosis
alternative explanation for dMMR CRC has
been confirmed through tumour testing i.e.,
MLH1 promoter methylation or biallelic
somatic variants
or germline causes for dMMR cannot be
identified despite exhaustive testing, therefore
LS cannot be confirmed or ruled-out
CRC dominant trait families who meet the
Amsterdam Criteria, regardless of identification
of dMMR. If a germline MMR mutation has
been identified, then these patients are more
commonly described as having Lynch
syndrome, however only ˜65% of HNPCC will
be due to LS
HNPCC with pMMR CRC, i.e., Lynch
syndrome has largely been excluded [32]
A genetic diagnosis of another syndrome <2
CRC (%)
12–15
9–12
1
<3
<2
Healthy Nevada Study in USA, identified 66 participants with LS, 1 in~ 340 [36].
The rate of oncological diagnoses was 28.8%.
As participants in both studies are not selected for family history, lower disease
penetrance is likely given a high population prevalence of PMS2 mutations which
is the most common genetic diagnosis in LS.
A large US study reviewed families of 5744 patients with CRC. They estimated
that 1 in 279 in this population had mutations in MMR genes and using estimates
of polygenic variance, they found unidentified major genes which may account for
1/3 to 1/2 of other factors in heritability of CRC [37].
4.2.3 Gene-Specific Cancer Risk
For individuals with LS there is variability in the risk of organ specific cancers
across their lifetime. The Prospective LS Database (PLSD) is a global collaboration of data from patients with LS, and this data has informed risk-stratification
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of patients by gene, age and gender [2]. The information is freely available as an
online tool for clinicians and patients at the website plsd.eu.
Lifetime risk in % (male; female; combined, up to age 75) [accessed Wednesday
19th July 2023] seen in Figs. 4.6, 4.7, 4.8 and 4.9.
The figure below demonstrates assessment for cumulative risk for different cancers dependent on pathogenic variant, sex and age, with recognition that this is
with assumed but unvalidated adherence to recommended surveillance.
The PLSD database provides useful tool to illustrate and support counselling
families with LS, however, there is observed variability in risk (Fig. 4.10). As with
any predictive tool, there are modifiers of cancer risk which cannot be accounted
for, including environment, lifestyle, polygenic risk factors, and incomplete data
which result in broad confidence intervals.
To elucidate this variability, the International Mismatch Repair Consortium,
reviewed 79,809 relatives (5255 families) where at least one member was a confirmed carrier of an MMR pathogenic variant [38]. They used segregation analysis
conditioned on ascertainment to review the penetrance of CRC as well as polygenic factors which may account for variation in penetrance. CRC rate variance
was seen in MLH1 and MSH2 carriers (which comprised the largest part of this
cohort) indicating that up to 56% of carriers had a CRC and up to 44% of carriers had a CRC penetrance of > 8. There was wide variation amongst carriers,
with some patients almost certain to get cancer and others closer to that of population risk. This is concordant with other familial cancer syndromes, for example
BRCA1/BRCA2 carriers where similar variation is shown [39]. A study of 3828
LS carriers at Dana-Faber Institute also concluded that familial burden, i.e., rates
of organ specific disease in individuals, first and second-degree relatives showed a
significant association of endometrial and urinary tract cancers [40].
Fig. 4.6 Organ specific lifetime risk in MLH1 carriers
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Fig. 4.7 Organ specific lifetime risk in MSH2 carriers
Fig. 4.8 Organ specific lifetime risk in MSH6 carriers
Polygenic risk scores (PRS) are calculated by reviewing single nucleotide polymorphisms (SNPs) which are used to identify persons in the general population
who are at greater risk of CRCs. Ultimately, a tool combining global environmental and other genetic factors which modify risk would be useful. PRS used to
identify risk of CRC in patients without LS has not been proven to be predictive
in LS from a study of 826 patients with LS, of whom 504 had developed CRC
[41], therefore further data is required to refine a PRS tool in LS.
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Fig. 4.9 Organ specific lifetime risk in PMS2 carriers
Fig.4.10 PLSD database provides regularly updated information on risk for different organs spe-
cific to genetic variant, age and sex. The drop-down boxes shown can allow selection for specific
patient or group to provide a more personalised risk [2]
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4.3 Diagnosis of Lynch Syndrome: MMR Testing
Somatic testing in colorectal and endometrial cancers: the pathway from cancer
to LS diagnosis
Testing cancers for MMR deficiency (dMMR) identifies patients who may be at
risk of LS who require further evaluation. Methods for detection of dMMR are
usually with either immunohistochemistry for MMR protein expression, or by
microsatellite instability (MSI) testing (PCR based test). As per NICE guidelines,
DG27 either test can be performed as an index test to identify dMMR CRC [42],
and patients who would benefit from further diagnostic testing for LS (Fig. 4.11).
Immunohistochemistry (IHC)
This test identifies loss of MMR protein expression in tumour tissue. This is a wellestablished and relatively inexpensive histopathological test for MLH1, MSH2,
MSH6 and PMS2 expression (Fig. 4.12).
Microsatellite instability (MSI) testing
MSI is a marker of replication mismatch errors and represents numbers of
indel mutations within a panel of typically 6–10 microsatellite (repetitive DNA
sequences) regions in tumours—these repetitive DNA sequences are prone to
replication errors and therefore useful markers of dMMR. Testing has categorised
tumours as; MSI-stable (MSS), MSI-low (MSI-L) if < 30% markers unstable or
MSI-high (MSI-H) > 30% markers unstable.
Discordance in MMR results between dMMR IHC and MSI-H
Generally, these two terms are used interchangeably and are often concordant. In
LS, dMMR is associated with MSI up to 98% in CRC, 94% in endometrial, however this differs in other LS tumours e.g., urothelial 23% and brain tumours [43].
An MSS phenotype has been found in 36% LS tumours—associated with nonendometrial, non-colorectal and PMS2 and MSH6 gene variants [43, 44]. However,
some MSS tumours in LS patients may be bystander ‘sporadic’ cancers.
Further somatic testing
Most patients with dMMR CRC do not have a germline MMR defect. Hyperand hypo- methylation of the cancer genome is a frequent somatic event in CRC
carcinogenesis, and methylation of CpG (5
-C-phosphate-G-3) rich gene promoter
regions results in reduced gene expression. MLH1 promoter methylation is present
in approximately 10% of sporadic CRC, and is increasingly common with age,
and is therefore more frequent in older CRC patients.
Somatic methylation of the MLH1 promoter results in loss of transcription
of the MLH1 gene, causing dMMR which does not represent LS (although an
inherited form of MLH1 promoter methylation may be present this is a rare manifestation). Therefore, where there is loss of expression of MLH1 protein on IHC,
or the identification MSI-H/L in tumour, the next step in the testing pathway is
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No further tesng
MLH1, MSH2, MSH6 or
PMS2 IHC result normal
abnormal
MSH2, MSH6 or
PMS2 IHC results
Do an IHC 4-panel test for MLH1, MSH2, MSH6 and PMS2
abnormal
MLH1 IHC result
or
(MSI-L or MSI-H)
Use clinical judgement to decide whether to test tumour
ssue from a biopsy, resected colorectal tumour or polyp
repair proteins or microsatellite instability (MSI) tesng to idenfy tumours with deficient DNA mismatch repair
Offer tesng to all people with colorectal cancer, when first diagnosed, using immunohistochemistry (IHC) for mismatch
MSI result posive
Do an MSI test
MSI result negave (MSS)
Test negave
Do a BRAF V600E test
Test posive
No further tesng
Test negave
tesng of germline DNA
Confirm Lynch syndrome by genec
Do an MLH1 promoter hypermethylaon test
tesng with people referred for DNA germline tesng
Test posive
Only appropriately trained healthcare professionals should discuss genec
Flowchart showing molecular tesng strategies for Lynch syndrome in people with colorectal cancer
Healthcare professionals must tell
relaves, and ensure that relevant
support and informaon is available
people about the possible implicaons
of test results for themselves and their
Abbreviaons: MSI-H, MSI-
High; MSI-L, MSI-Low; MSS ,
microsatellite stable.
Fig.4.11 NICE guidelines flowchart testing strategies for Lynch syndrome [42]. NICE 2017 Flowchart showing molecular testing strategies for Lynch syndrome
in people with colorectal cancer. Available from https://www.nice.org.uk/guidance/dg27/resources/testing-strategies-flowchart-4367005453. All rights reserved.
Subject to Notice of rights. NICE guidance is prepared for the National Health Service in England. All NICE guidance is subject to regular review and maybe
updated or withdrawn. NICE accepts no responsibility for the use of its content in this product/publication
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