Cancer risk in MLH1, MSH2 and MSH6 mutation carriers; different risk profiles may influence clinical management.

Abstract

Lynch syndrome (LS) is associated with a high risk for colorectal cancer (CRC) and extracolonic malignancies, such as endometrial carcinoma (EC). The risk is dependent of the affected mismatch repair gene. The aim of the present study was to calculate the cumulative risk of LS related cancers in proven MLH1, MSH2 and MSH6 mutation carriers.
The studypopulation consisted out of 67 proven LS families. Clinical information including mutation status and tumour diagnosis was collected. Cumulative risks were calculated and compared using Kaplan Meier survival analysis.
MSH6 mutation carriers, both males and females had the lowest risk for developing CRC at age 70 years, 54% and 30% respectively and the age of onset was delayed by 3-5 years in males. With respect to endometrial carcinoma, female MSH6 mutation carriers had the highest risk at age 70 years (61%) compared to MLH1 (25%) and MSH2 (49%). Also, the age of EC onset was delayed by 5-10 years in comparison with MLH1 and MSH2.
Although the cumulative lifetime risk of LS related cancer is similar, MLH1, MSH2 and MSH6 mutations seem to cause distinguishable cancer risk profiles. Female MSH6 mutation carriers have a lower CRC risk and a higher risk for developing endometrial carcinoma. As a consequence, surveillance colonoscopy starting at age 30 years instead of 20-25 years is more suitable. Also, prophylactic hysterectomy may be more indicated in female MSH6 mutation carriers compared to MLH1 and MSH2 mutation carriers.

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BioMed Central
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Hereditary Cancer in Clinical
Practice
Open Access
Research
Cancer risk in MLH1, MSH2 and MSH6 mutation carriers; different
risk profiles may influence clinical management
Dewkoemar Ramsoekh*1,2, Anja Wagner3, Monique E van Leerdam1,
Dennis Dooijes3, Carli MJ Tops4, Ewout W Steyerberg2 and Ernst J Kuipers1,5
Address: 1Department of Gastroenterology and Hepatology Erasmus MC University Medical Center, PO Box 2040, 3000 CA, Rotterdam, the
Netherlands, 2Department of Public Health, Erasmus MC University Medical Center, PO Box 2040, 3000 CA, Rotterdam, the Netherlands,
3Department of Clinical Genetics, Erasmus MC University Medical Center, PO Box 2040, 3000 CA, Rotterdam, the Netherlands, 4Department of
Human and Clinical Genetics, Leiden University Medical Center, PO Box 9600, 2300 RC Leiden, the Netherlands and 5Department of Internal
Medicine, Erasmus MC University Medical Center, PO Box 2040, 3000 CA, Rotterdam, the Netherlands
Email: Dewkoemar Ramsoekh* - d.ramsoekh@erasmusmc.nl; Anja Wagner - a.wagner@erasmusmc.nl; Monique E van
Leerdam - m.vanleerdam@erasmusmc.nl; Dennis Dooijes - d.dooijes@erasmusmc.nl; Carli MJ Tops - C.M.J.Tops@lumc.nl;
Ewout W Steyerberg - e.steyerberg@erasmusmc.nl; Ernst J Kuipers - e.j.kuipers@erasmusmc.nl
* Corresponding author
Abstract
Background: Lynch syndrome (LS) is associated with a high risk for colorectal cancer (CRC) and
extracolonic malignancies, such as endometrial carcinoma (EC). The risk is dependent of the
affected mismatch repair gene. The aim of the present study was to calculate the cumulative risk
of LS related cancers in proven MLH1, MSH2 and MSH6 mutation carriers.
Methods: The studypopulation consisted out of 67 proven LS families. Clinical information
including mutation status and tumour diagnosis was collected. Cumulative risks were calculated and
compared using Kaplan Meier survival analysis.
Results: MSH6 mutation carriers, both males and females had the lowest risk for developing CRC
at age 70 years, 54% and 30% respectively and the age of onset was delayed by 3-5 years in males.
With respect to endometrial carcinoma, female MSH6 mutation carriers had the highest risk at age
70 years (61%) compared to MLH1 (25%) and MSH2 (49%). Also, the age of EC onset was delayed
by 5-10 years in comparison with MLH1 and MSH2.
Conclusions: Although the cumulative lifetime risk of LS related cancer is similar, MLH1, MSH2
and MSH6 mutations seem to cause distinguishable cancer risk profiles. Female MSH6 mutation
carriers have a lower CRC risk and a higher risk for developing endometrial carcinoma. As a
consequence, surveillance colonoscopy starting at age 30 years instead of 20-25 years is more
suitable. Also, prophylactic hysterectomy may be more indicated in female MSH6 mutation carriers
compared to MLH1 and MSH2 mutation carriers.
Background
Lynch syndrome (LS), also known as hereditary non-poly-
posis colorectal cancer, is the most common hereditary
colorectal cancer (CRC) syndrome and accounts for 2-5%
of all colorectal cancer cases [1]. Germline mutations in
any of the four mismatch repair (MMR) genes, MLH1[2],
Published: 23 December 2009
Hereditary Cancer in Clinical Practice 2009, 7:17doi:10.1186/1897-4287-7-17
Received: 28 July 2009
Accepted: 23 December 2009
This article is available from: http://www.hccpjournal.com/content/7/1/17
© 2009 Ramsoekh et al; licensee BioMed Central Ltd.
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0),
which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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MSH2[3], MSH6[4] and PMS2[5], are the underlying
cause of LS. Subjects carrying a mutation in one of the
MMR genes have a higher risk for developing colorectal
cancer, but also for endometrial carcinoma and malignan-
cies of the stomach, small bowel, ovaries, upper uroepi-
thelial tract, biliary tract, skin and brain [6-9].
The colorectal cancer risk in LS is dependent on sex and
the MMR gene involved. The reported lifetime risk for
colorectal cancer in the literature varies from 28-100% in
males and 25-83% in females [7,10-18]. The risk of devel-
oping endometrial carcinoma ranges from 30-71% and
the risk of other LS-associated cancers is less than 10-15%
[9]. Furthermore, some studies have suggested that extra-
colonic cancers are more often observed in MSH2 muta-
tion families compared to MLH1 mutation families
[13,19]. MSH6 mutation families probably have a milder
clinical phenotype with a later onset of both CRC and EC
and clustering of endometrial carcinoma [17]. The risks in
PMS2 mutation families are largely unknown. One study
reported that PMS2 mutation families have a milder phe-
notype compared to MLH1 and MSH2 families [20].
Unfortunately, the precise lifetime risk for CRC and
endometrial carcinoma may be biased because the fami-
lies selected in previous studies were mainly selected on
basis of clustering of CRC or fulfilment of clinical criteria
(Amsterdam II criteria). Furthermore, it was not always
clear whether the affected subjects were proven mutation
carriers. In addition, most studies have only evaluated
lifetime risks for MLH1 and MSH2 mutations, while stud-
ies evaluating MSH6 mutation families are sparse. The
most efficient way to calculate the lifetime risks of CRC
and EC in Lynch syndrome would be to calculate these
risks based on a cohort of proven mutation carriers. There-
fore, the aim of the present study was to calculate the
cumulative lifetime risks for CRC and EC in Lynch syn-
drome using a cohort of proven MLH1, MSH2 and MSH6
mutation carriers.
Methods
Study population
During the period 1994-2007, an MMR gene mutation
was detected in 67 families who were counselled at the
Department of Clinical Genetics of the Erasmus MC Uni-
versity Medical Center, because of a clinical suspicion for
Lynch syndrome. Clinical data of family members includ-
ing sex, age, mutation status, age at diagnosis of both LS-
associated and other cancers were collected. LS-associated
cancer included colorectal, endometrial, stomach, ovaries,
upper uroepithelial tract, biliary tract, skin and brain can-
cer. Also, the site of the tumour, age at death and cause of
death were collected. With consent of the patients or (in
case the patient was deceased) of a close relative the cancer
diagnosis was confirmed by pathology and/or medical
reports. All pathology and medical reports were reviewed
by the first author (DR) in order to confirm the diagnosis.
If a subject reported the occurrence of cancer in the family
and no pathology or medical report was available, the
cancer was excluded from analysis. In addition, data
regarding colonoscopic surveillance of affected and unaf-
fected family members were collected.
Only subjects with a proven MMR gene mutation were
included in this study.
Mutation analysis
Mutation analysis was performed by denaturing gradient
gel electrophoresis, sequencing and multiplex ligation-
dependent probe amplification (MRC-Holland kits P003
and P008). Mutation nomenclature was used according to
international guidelines http://www.hgvs.org. A variant
was considered a mutation when leading to a predicted
truncated protein or based on previously published data.
Silent or missense variants which were previously unre-
ported or of unclear status were labelled unclassified vari-
ants (UV) and not considered as an MMR gene mutation.
Statistical analysis
Data were submitted for statistical testing using the Statis-
tical Package for the Social Sciences (SPSS Inc, Chicago,
IL), version 12.0.1. Data are given as median and range or
as mean with standard deviation when appropriate. The
chi square test, Student's t test and log rank test were used
to compare differences between MLH1, MSH2 and MSH6
mutation carriers. Penetrance for age was calculated using
the Kaplan Meier survival analysis method and included
the 67 index cases. In case of multiple or recurrent color-
ectal carcinoma or endometrial adenocarcinoma, only the
first diagnosis of either cancer was included in the analy-
sis. The observation time for the different cancers was
from birth until the date of first cancer diagnosis, death,
date of hysterectomy (only for the observation time of
endometrial carcinoma) or the end of the study (31
December 2007). A p value below .05 was considered sta-
tistically significant.
Results
Study population
In the 67 families with an MMR gene mutation, 26 (39%)
were detected with an MLH1 mutation, 20 (30%) with an
MSH2 mutation and 21 (31%) with an MSH6 mutation.
Of the 67 families, 46 (69%) met the Amsterdam II crite-
ria. Mutation analysis was performed in 725 subjects (296
men and 429 women) and a mutation was identified in
246 subjects (92 men, 154 women) (Table 1). At the time
of mutation analysis the mean age of the 246 mutation
carriers was 49 (± 16) years. Of the 246 mutation carriers,
115 (47%) were diagnosed with a Lynch syndrome asso-
ciated tumour. One hundred and four (42%) mutation

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carriers already had been diagnosed with a Lynch syn-
drome associated tumour before mutation analysis was
performed. Colorectal cancer was diagnosed in 83 (34%)
mutation carriers, including 17 (7%) mutation carriers
who developed 2 or more CRCs during their lifetime.
Endometrial carcinoma was diagnosed in 37 (24%) of the
154 female mutation carriers, including 13 mutation car-
riers who also developed CRC during their life. Of the six
families with a strong family history of endometrial carci-
noma (two or more cases within the family), five (83%)
were diagnosed with an MSH6 mutation. With respect to
the other LS-associated cancers, 19 (8%) mutation carriers
developed another LS-associated cancer during their life
(Table 1). Seven of these nineteen mutation carriers were
also diagnosed with CRC, one mutation carrier also with
endometrial carcinoma and four mutation carriers with
both CRC and EC. In total, 194 mutation carriers were
under colonoscopic surveillance, including 69 subjects
who had already been diagnosed with colorectal cancer
before mutational testing was performed.
One of the 69 mutation carriers had previously been diag-
nosed with EC and developed CRC while being under
colonoscopic surveillance. The other 68 mutation carriers
were included in a colonoscopic surveillance program
after being diagnosed with colorectal cancer. These 68
subjects were treated surgically (partial colectomy) for
colorectal cancer and colonoscopic surveillance of the
remaining colon was performed. Of the remaining 125
mutation carriers none developed colorectal cancer and in
23 (18%) adenomatous polyps had been detected and
removed. The person-years of follow up was 1414 years
and the mean follow up time of the subjects under colon-
oscopic surveillance was 7 ± 4 years.
Lifetime risks
The respective lifetime risks curves are shown in figure 1,
figure 2, figure 3 and figure 4. For all LS-associated
tumours, the cumulative risks in both male and female
mutation carriers at 70 years was 71% for MLH1, 77% for
MSH2 and 75% for MSH6 mutation carriers (Figure 1).
Although the cumulative risks at age 70 years were similar
for the three different MMR genes, the log rank test
showed a significant difference for developing any Lynch
syndrome associated cancer between MSH6, MLH1 and
MSH2 mutation carriers (p = 0.01). This was due to the
fact that before the age of 70 years the risk of developing
any Lynch syndrome associated cancer in MSH6 carriers
was lower compared to MLH1 or MSH2 mutation carriers
(Figure 1).
Table 1: Study population characteristics
MLH1MSH2 MSH6Total
Families
Mutation carriers
Males (%)
26
70
20
67
21
109
36 (33)
67
246
92 (37) 28(40)28 (42)
Subjects with colorectal cancer (%)
Subjects with endometrial carcinoma
36 (51)
7 (10)
21 (31)
9 (13)
26 (24)
21 (19)
83 (34)
37 (15)
Subjects with other Lynch associated cancer (%)*
Ovarian carcinoma
Small bowel cancer
Transitional cell carcinoma
1 (1)
1 (1)
0 (0)
3 (4)
2 (3)
3 (4)
6 (6)
0 (0)
3 (3)
10 (4)
3 (1)
6 (2)
* No histological proven stomach cancers were reported.
All Lynch associated cancers (colorectal, endometrial, stom-ach, ovaries, upper uroepithelial tract, biliary tract, skin and brain cancer): cumulative risks for MLH1, MSH2 and MSH6
mutation carriers
Figure 1
All Lynch associated cancers (colorectal, endome-
trial, stomach, ovaries, upper uroepithelial tract, bil-
iary tract, skin and brain cancer): cumulative risks for
MLH1, MSH2 and MSH6 mutation carriers.

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In Figure 2, the age related cumulative risk for CRC is
shown for male MLH1, MSH2 and MSH6 mutation carri-
ers. At age 70 years, the cumulative risk was the highest for
MLH1 mutation carriers, 78%, while the cumulative risks
for MSH2 and MSH6 mutation carriers were 57% and
54% respectively. There was no significant difference in
age related cumulative risk between MSH6 mutation car-
riers (p = 0.05) compared to MLH1 and MSH2 mutation
carriers. However, the highest increase in risk in male
MLH1 and MSH2 mutation carriers was observed between
the ages of 40 to 50 years, while the risk in male MSH6
mutation carriers mostly increased between the ages of 50
to 60 years. Although the age related risks were not signif-
icant different between the three different MMR genes,
there was a trend in male MLH1 and MSH2 mutation car-
riers to develop CRC at an earlier age than male MSH6
mutation carriers. The cumulative risks for CRC in females
were lower compared to males, 57% for MLH1, 52% for
MSH2 and 30% for MSH6 mutation carriers (Figure 3),
with a significantly lower age related cumulative risk in
MSH6 mutation carriers (p = 0.001) compared to MLH1
and MSH2 mutation carriers.
For endometrial carcinoma, the highest cumulative risk
was observed in the MSH6 mutation carriers (61%), while
the cumulative risks for MLH1 and MSH2 mutation carri-
ers were 25% and 49% respectively. However, the log rank
test showed no significant difference in age related cumu-
lative risk (p = 0.58) between MSH6 mutation carriers
compared to MLH1 and MSH2 mutation carriers.
Median age of onset
The median age of CRC onset in males was significantly
higher in MSH6 mutation carriers (48 years; range 32-84
years) compared to MSH2 mutation carriers (43 years;
range 20-51 years, p = 0.03), but not significantly higher
compared to MLH1 mutation carriers (45 years; range 33-
63 years, p = 0.07) (Table 2). For female mutation carriers,
no significant differences in the median age of CRC onset
were found when comparing MSH6 (53 years; range 34-
61 years) with MLH1 (50 years; range 25-79 years, p =
0.88) and MSH2 (44 years; range 29-82 years, p = 0.28).
The median age of EC onset was significant higher in
MSH6 mutation carriers (56 years; 47-67 years) compared
to MLH1 mutation carriers (51 years; 46-54 years, p =
0.02) and MSH2 mutation carriers (46 years; 36-55 years,
p = 0.001). There were no significant differences in the age
of onset of other LS-associated cancers between MLH1 (53
years; range 52-54 years), MSH2 (42 years; range 23-59
years) and MSH6 (50 years; range: 35-76) mutation carri-
ers (MLH1 vs. MSH2, p = 0.41; MLH1 vs. MSH6, p = 0.76
and MSH2 vs. MSH6, p = 0.41).
Discussion
In this study, we evaluated 246 individuals from 67 fami-
lies with a proven mismatch repair gene mutation to
determine the cumulative lifetime risk of developing can-
Colorectal cancer in males; cumulative risks for MLH1,
MSH2 and MSH6 mutation carriers
Figure 2
Colorectal cancer in males; cumulative risks for MLH1,
MSH2 and MSH6 mutation carriers.
Colorectal cancer in females, cumulative risks for MLH1,
MSH2 and MSH6 mutation carriers
Figure 3
Colorectal cancer in females; cumulative risks for MLH1,
MSH2 and MSH6 mutation carriers.

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cer. Previous studies have shown different lifetime risks
for developing CRC in Lynch patients.
One of the first studies evaluating the lifetime risk
reported a lifetime risk for CRC at age 75 years of 92% in
males and 83% in females [10]. Most later studies
reported somewhat similar risks for CRC ranging from 65-
100% in males and 30-63% risk in females [7,11-13]. A
more recently published study reported the lowest life-
time risk for CRC so far, 27% for males and 22% for
females at age 70 years [15]. All these studies only evalu-
ated the risks associated with MLH1 and MSH2 muta-
tions. Thirty one percent of the families included in our
study carried an MSH6 mutation. This frequency is higher
than previously reported [4,21-23]. Studies evaluating the
lifetime risks of cancer amongst MLH1, MSH2 and MSH6
families are sparse. A study evaluating the risk in 20 MSH6
families showed that colorectal cancer was less frequent
and developed 10 years later in MSH6 compared to MLH1
and MSH2. In addition a significant higher lifetime risk of
endometrial carcinoma of 71% in MSH6 mutation carri-
ers with a later age of onset (54 years vs. 48 and 49 years
for MLH1 and MSH2) was reported [17]. A German study
comparing 27 MSH6 mutation families with 156 MLH1
and MSH2 mutation families confirmed the lower risk
and later age of onset of CRC in MSH6 families [24].
These results were also confirmed by a recently published
British study, but this study only included 11 proven
MSH6 mutation carriers [18].
Our study indicates that, however the cumulative risks of
cancer at age 70 years in MLH1, MSH2 and MSH6 muta-
tion carriers is similar, each mutated gene has a distin-
guishable cancer risk profile. In MSH6 mutation carriers
the risk at age 70 years for developing CRC was the lowest
in both male (54%) and female (30%) when compared to
carriers of MLH1 and MSH2 mutations.
Between male MSH6 and MSH2 mutation carriers also a
significant difference in the age of CRC onset (48 vs. 43
years, p = 0.03) was found and there was a trend in higher
age of CRC onset between male MSH6 and MLH1 muta-
tion carriers. For female mutation carriers, no significant
differences were found in the mean age of onset of CRC.
This can be explained by the fact that female MLH1 and
MSH2 mutation carriers still developed CRC at an older
age. The lower risk of CRC onset in female MSH6 muta-
tion carriers under the age of 50 years raises the question
whether colonoscopic surveillance guidelines in these
subjects can be changed. Current guidelines advise to start
with biennial colonoscopy surveillance from the age of
20-25 years [25]. In our study population, the youngest
affected female MSH6 mutation carrier with CRC was 34
years. Our data and the data from previous studies sup-
port that colonoscopic surveillance can be started at an
age of 30 years in female MSH6 mutation carriers [17].
However our numbers are too small to draw definite con-
clusions, CRC seems to be the predominant cancer in
MLH1 mutation carriers. In MSH2 and MSH6 mutation
carriers extracolonic cancers appear to contribute more to
the similar cumulative lifetime risk of cancer in MLH1,
MSH2 and MSH6 mutation carriers. A higher risk of extra-
colonic-LS-associated cancer was previously reported in
MSH2 mutation carriers compared to MLH1 mutation
carriers [13,19]. Unfortunately, the number of extraco-
lonic-LS associated cancer (excluding endometrial carci-
noma) in our study population was too low to calculate
accurate risk estimates for these cancers. In concordance
with other studies [17,26] our study indicates that MSH6
carriers have the highest endometrial cancer risk followed
by MSH2 and MLH1 mutation carriers. Also, this risk
increases sharply after the age of 50 years. In view of the
disputable effect of endometrial carcinoma surveillance
[27,28], in female MSH6 carriers aged 45 years or above
prophylactic hysterectomy may be suggested in order to
decrease the risk for developing endometrial carcinoma
[29]. In MSH2 and MLH1 female mutation carriers this
option may be more questionable. In MSH2 mutation
carriers the risk of other extracolonic and extraendome-
trial cancers may reduce faith in and benefit of risk reduc-
ing surgery. In MLH1 mutation carriers the risk of
endometrial cancer may not outweigh the disadvantages
of surgery. In case of surgery for another cause, additional
hysterectomy should be considered also in MLH1 en
MSH2 mutation carriers.
Endometrial carcinoma in females, cumulative risks for
MLH1, MSH2 and MSH6 mutation carriers
Figure 4
Endometrial carcinoma in females; cumulative risks for
MLH1, MSH2 and MSH6 mutation carriers.

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A strength of the present study was that the age related
risks where calculated using proven mutation carriers.
However, the age related risks might be somewhat lower
since not all the unaffected individuals from proven
mutation families opted for genetic testing and thus the
total number of unaffected mutation carriers in the muta-
tion families may be underestimated. In addition, indi-
viduals with a higher risk for mutation carriership, i.e.
with an affected first degree relative, more often opt for
genetic testing [30]. This may also have introduced some
bias with respect to the age related risks. Also, we included
the index cases in our study population. Index cases give
rise to the suspicion of Lynch syndrome and they always
have cancer. This may also have resulted in a slightly
higher age related risk. On the other hand, the majority
(77%) of not affected mutation carriers was under colon-
oscopy surveillance, which likely has influenced the age
related risks for developing invasive CRC, since colonos-
copy surveillance in Lynch syndrome patients is effective
in reducing the incidence and mortality of CRC [31]. A
limitation of our study was that our study population was
not very large (n = 246), and the number of male carriers
was 92. This could explain why we did not find a signifi-
cant difference in both the mean age of CRC onset and the
age related risk between male MLH1, MSH2 and MSH6
mutation carriers.
In conclusion, the present study indicates that, although
the cumulative risks at age 70 years of LS related cancer in
MLH1, MSH2 and MSH6 mutation carriers are similar,
each mutated gene has a distinguishable cancer risk pro-
file. It underlines that female MSH6 mutation carriers
have a distinct clinical phenotype with a lower CRC risk
and a higher risk for developing endometrial carcinoma.
Starting with biennial colonoscopic surveillance at an age
of 30 years instead of an age of 20-25 years in female
MSH6 mutation carriers is more suitable. Moreover, in
female MSH6 mutation carriers prophylactic hysterec-
tomy may be considered from an age of 45 years.
Conclusions
The present study indicates that each mutated MMR gene
has a distinguishable cancer risk profile. Female MSH6
mutation carriers have a lower CRC risk and a higher risk
for developing endometrial carcinoma. Starting with
biennial colonoscopic surveillance at an age of 30 years in
female MSH6 mutation carriers is more suitable and pro-
phylactic hysterectomy may be considered from an age of
45 years.
Abbreviations
CRC: colorectal cancer; EC: endometrial cancer; LS: Lynch
syndrome; MMR: mismatch repair; UV: unclassified vari-
ant.
Competing interests
The authors declare that they have no competing interests.
Authors' contributions
DR participated in the data collection, performed the sta-
tistical analyses and helped to draft the manuscript. AW
conceived of the study and participated in the data collec-
tion. ML helped to draft the manuscript. DD participated
in the data collection. CT participated in the data collec-
tion. ES participated in the design of the study and
assisted in the statistical analysis. EK helped to draft the
manuscript. All authors read and approved the final man-
uscript.
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MLH1MSH2MSH6
Colorectal cancer
Endometrial cancer
Ovarian carcinoma
Small bowel cancer
Transitional cell carcinoma
47 (25-79)
51 (46-54)
52 (52-52)
54 (54-54)
-
44 (20-82)
46 (36-55)
47 (45-48)
36 (23-49)
58 (32-59)
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-

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