JNCI | Articles 193
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Lynch syndrome, also known as hereditary nonpolyposis colon
cancer syndrome (1), is a rare, autosomal, dominantly inherited
syndrome caused by germline mutations in DNA mismatch repair
genes, which confer substantial risks for cancers of the colorectum
and endometrium and increased risks for cancers of the stomach,
small intestine, hepatobiliary system, kidney, ureter, ovary, and
sebaceous tumors (2,3). Mutations in the mismatch repair genes,
MLH1 and MSH2, account for 70%–80% of all Lynch syndrome
colorectal cancers (ie, colorectal cancers occurring in people with
germline DNA mismatch repair gene mutations) (4–7).
Mutations in MSH6 account for 10%–20% of Lynch syndrome
colorectal cancers and 0.4% of all colorectal cancers (4–7), with
the greater proportion of colorectal cancer diagnosed at a
younger age (4,6). The prevalence of MSH6 mutations in women
with endometrial cancer who were not selected for family history
is less well established with estimates ranging from 1.0% to 3.8%
Few studies have attempted to estimate the age-specific cumu-
lative cancer risk for carriers of germline mutations in MSH6
(penetrance) (13–18), so information on the consequences of such
mutations remains uncertain. Most of these studies (13–16) have
analyzed data from families that were ascertained because of a
strong family history of cancers related to Lynch syndrome, or
preferentially mutation-tested individuals with colorectal cancer
over individuals without colorectal cancer, and appear not to have
correctly taken into account the ascertainment when deriving their
penetrance estimates. Recruiting families from family cancer
clinics will result in oversampling of family members who have
been diagnosed with colorectal or other cancers, and such recruit-
ment has been shown to result in inflated estimates of cancer risks
risks of lynch Syndrome cancers for MSH6 Mutation carriers
Laura Baglietto, Noralane M. Lindor, James G. Dowty, Darren M. White, Anja Wagner, Encarna B. Gomez Garcia, Annette
H. J. T. Vriends, Dutch Lynch Syndrome Study Group, Nicola R. Cartwright, Rebecca A. Barnetson, Susan M. Farrington,
Albert Tenesa, Heather Hampel, Daniel Buchanan, Sven Arnold, Joanne Young, Michael D. Walsh, Jeremy Jass, Finlay Macrae,
Yoland Antill, Ingrid M. Winship, Graham G. Giles, Jack Goldblatt, Susan Parry, Graeme Suthers, Barbara Leggett, Malinda Butz,
Melyssa Aronson, Jenny N. Poynter, John A. Baron, Loic Le Marchand, Robert Haile, Steve Gallinger, John L. Hopper,
John Potter, Albert de la Chapelle, Hans F. Vasen, Malcolm G. Dunlop, Stephen N. Thibodeau, Mark A. Jenkins
Manuscript received June 9, 2009; revised November 10, 2009; accepted November 17, 2009.
Correspondence to: Noralane M. Lindor, MD, E7B, Mayo Foundation, Rochester, MN 55905 (e-mail: firstname.lastname@example.org).
Background Germline mutations in MSH6 account for 10%–20% of Lynch syndrome colorectal cancers caused by hereditary
DNA mismatch repair gene mutations. Because there have been only a few studies of mutation carriers, their
cancer risks are uncertain.
Methods We identified 113 families of MSH6 mutation carriers from five countries that we ascertained through family can-
cer clinics and population-based cancer registries. Mutation status, sex, age, and histories of cancer, polypectomy,
and hysterectomy were sought from 3104 of their relatives. Age-specific cumulative risks for carriers and hazard
ratios (HRs) for cancer risks of carriers, compared with those of the general population of the same country, were
estimated by use of a modified segregation analysis with appropriate conditioning depending on ascertainment.
Results For MSH6 mutation carriers, the estimated cumulative risks to ages 70 and 80 years, respectively, were as fol-
lows: for colorectal cancer, 22% (95% confidence interval [CI] = 14% to 32%) and 44% (95% CI = 28% to 62%) for
men and 10% (95% CI = 5% to 17%) and 20% (95% CI = 11% to 35%) for women; for endometrial cancer, 26%
(95% CI = 18% to 36%) and 44% (95% CI = 30% to 58%); and for any cancer associated with Lynch syndrome, 24%
(95% CI = 16% to 37%) and 47% (95% CI = 32% to 66%) for men and 40% (95% CI = 32% to 52%) and 65% (95%
CI = 53% to 78%) for women. Compared with incidence for the general population, MSH6 mutation carriers had
an eightfold increased incidence of colorectal cancer (HR = 7.6, 95% CI = 5.4 to 10.8), which was independent of
sex and age. Women who were MSH6 mutation carriers had a 26-fold increased incidence of endometrial can-
cer (HR = 25.5, 95% CI = 16.8 to 38.7) and a sixfold increased incidence of other cancers associated with Lynch
syndrome (HR = 6.0, 95% CI = 3.4 to 10.7).
Conclusion We have obtained precise and accurate estimates of both absolute and relative cancer risks for MSH6 mutation
J Natl Cancer Inst 2010;102:193–201
194 Articles | JNCI Vol. 102, Issue 3 | February 3, 2010
if this ascertainment is not fully taken into account (19). For pop-
ulation-based studies, the appropriate adjustment for ascertain-
ment is straightforward. A meta-analysis (18) of 10 MSH6 mutation
families extracted from two population-based studies (17,20) esti-
mated that the cumulative colorectal cancer risk to age 70 years
was similar for men and women at approximately 35%. For endo-
metrial cancer, the cumulative risk was approximately 35% to age
70 years and 50% to age 80 years. In this analysis, we combined
data from 113 families with deleterious germline MSH6 mutations
and estimated the cancer risks for mutation carriers by use of sta-
tistical methods that appropriately condition on ascertainment.
Participants and Methods
The study population was composed of families that carried dele-
terious MSH6 mutations, which were defined as variants that were
predicted to result in a stop codon, a frameshift mutation, a large
insertion or deletion, or a missense mutation that was judged to be
deleterious. Families were obtained from four sources: 1) the
Colon Cancer Family Registry, which recruited colorectal cancer
families from the United States, Canada, Australia, and New
cONteXt AND cAVeAtS
Germline mutations in MSH6 account for 10%–20% of Lynch
syndrome colorectal cancers and approximately 0.4% of all colo-
Families of MSH6 mutation carriers from five countries were iden-
tified through family cancer clinics and population-based cancer
registries. Mutation status; sex; age; and histories of cancer,
polypectomy, and hysterectomy were sought from their relatives.
Age-specific cumulative risks of all Lynch syndrome cancers
among carriers were estimated.
MSH6 mutation carriers had high estimated cumulative risks to age
80 years for colorectal cancer, endometrial cancer, and any cancer
associated with Lynch syndrome. Compared with incidence for the
general population, MSH6 mutation carriers had an eightfold
increased incidence of colorectal cancer that was independent of
sex and age. Women who were MSH6 mutation carriers had a
26-fold increased incidence of endometrial cancer and a sixfold
increased incidence of other cancers associated with Lynch
The elevated risks for Lynch syndrome cancers in MSH6 mutation
carriers differed by sex of the carrier and continued into older age.
Screening for Lynch syndrome cancers in MSH6 mutation carriers
No haplotype analysis was done for any of the mutations identified
in more than one family.
From the Editors
Zealand; 2) a research consortium in the Netherlands; 3) a research
group in Scotland; and 4) a research group in Columbus, Ohio.
Probands, who were defined as the first person in the family to be
identified with a mutation in MSH6, were ascertained via popula-
tion-based cancer registries (ie, population-based probands) or
from family genetic services or cancer clinics (ie, clinic-based pro-
bands). From these sources, 113 families of MSH6 mutation car-
riers were ascertained for this study. Mutation status; sex; age; and
histories of cancer, polypectomy, and hysterectomy were sought
from the 3104 relatives of the 113 MSH6 mutation–carrying pro-
bands. Written informed consent was obtained, and this research
was approved by local institutional review boards at each recruiting
Colon Cancer Family Registry. Details of recruitment methods
have been described previously (21). All probands and families in
this study were recruited from January 1, 1997, through December
31, 2002. For clinic-based ascertainment, the probands were se-
lected from multiple-case colorectal or Lynch syndrome cancer
families who attended cancer clinics in the United States (Mayo
Clinic, Rochester, Minnesota; and Cleveland) and Australasia
(Melbourne, Adelaide, Perth, Brisbane, Sydney, Australia; and
Auckland, New Zealand). Probands were not required to have
colorectal cancer. For population-based ascertainment, probands
were defined as patients with newly diagnosed colorectal cancer
who were identified by population-based cancer registries in the
United States (Puget Sound, Washington; the State of Minnesota;
Los Angeles, California; Arizona; Colorado; New Hampshire;
North Carolina; and Hawaii), Australia (Victoria), and Canada
(Ontario). Most population-based sampling was independent of
family history but in some instances was stratified by family his-
tory. Relatives were recruited via the probands. Selection of pro-
bands for MSH6 gene analysis was based on the absence of MSH6
protein expression in tumor tissue. The immunohistochemistry
staining protocol has been described previously (22). Mutation
analysis of the MSH6 gene was performed by DNA sequence
analysis. Briefly, all 10 exons and flanking intron sequences of
MSH6 were amplified from genomic DNA in eight amplicons di-
vided into two multiplex polymerase chain reactions. Primers were
designed from the MSH6 human genomic sequence (GenBank
accession number NT_022184) and are available from the authors
upon request. Polymerase chain reaction multiplex-1 amplified
exons 2, 5, 6, 7, and 8–10 and multiplex-2 amplified exons 1, 3, and
4. Electrophoresis was performed on the ABI 3730 (Applied
Biosystems Inc, Foster City, CA). Sequence chromatograms were
analyzed by use of Mutation Surveyor (SoftGenetics, State College,
PA) software. Large insertions and deletions were detected by
multiplex ligation-dependent probe amplification (23).
Netherlands. Details of recruitment methods have been described
previously (24). Probands were selected from families suspected of
having Lynch syndrome by the Dutch Lynch Syndrome Study
Group from a national registry for families with hereditary non-
polyposis colon cancer established in the Netherlands in 1987.
Clinical information including age at diagnosis of cancer, site of
the tumor, and age at and cause of death was collected by the reg-
istry. Most probands were tested for MSH6 mutations depending
JNCI | Articles 195
on tumor microsatellite instability or mismatch repair protein ex-
pression. Polymerase chain reaction was used to amplify DNA.
In most laboratories in the Netherlands, indirect techniques such
as denaturing gradient gel electrophoresis, protein truncation test,
or more recently high-resolution melting curve analysis are, or
were, used to identify DNA variants. The fragments with variants
are subsequently analyzed by a direct DNA sequence analysis as
described above, and deletions and duplications were identified by
use of multiplex ligation-dependent probe amplification (13).
Scotland. Details of recruitment methods have been described
previously (6). All probands and families in this study were
recruited from January 1, 1999, through December 31, 2003.
Probands were identified from the Scottish Cancer Registry and
were defined as patients with newly diagnosed colorectal cancer or
endometrial cancer who were younger than 55 years when diag-
nosed and whose cancer was diagnosed in Scotland. Relatives were
recruited via the probands.
All probands were tested for MSH6 mutations irrespective of
tumor microsatellite instability or mismatch repair protein expres-
sion. Mutation analysis of the MSH6 gene was performed by DNA
sequence analysis, and large insertions and deletions were detected
by multiplex ligation-dependent probe amplification (6).
Ohio. Details of recruitment methods have been described previ-
ously (5,9). Probands were defined as individuals with newly diag-
nosed adenocarcinoma of the colorectum or endometrium,
regardless of age or family history of cancer, who were treated at
one of six major participating hospitals in Columbus, Ohio, in-
cluding the Ohio State University Medical Center (the James
Cancer Hospital and the Ohio State University East), Mount
Carmel East, Mount Carmel West, St Ann’s Hospital, Riverside
Methodist Hospital, and Grant Medical Center. In total, 1566
patients with colorectal cancer were recruited from January 1,
1999, through August 31, 2004.
All probands with colorectal or endometrial cancer with micro-
satellite instability were tested for germline mutations in MSH6.
Mutation analysis of the MSH6 gene was performed by DNA
sequence analysis, and large insertion and deletions were detected
by multiplex ligation-dependent probe amplification (5,9).
Information on demography, personal and family history of can-
cer, cancer screening, and cancer surgery was obtained from all
participants by interview, questionnaire, or extraction from clinical
records. Efforts were made to verify reported cancer diagnoses by
use of multiple sources, including family reporting, pathology
reports, medical records, and death certificates. All probands and
selected relatives were asked to provide a blood sample for DNA
analysis and to sign a consent to allow us to retrieve archived
colorectal cancer tissue.
We estimated the age-specific cumulative risk (penetrance) and the
age-specific hazard ratios (HRs) for mutation carriers compared
with the population for the following cancer groups: colorectal
cancer, endometrial cancer, all other Lynch cancers (ie, gastric,
small bowel, kidney, ureter, brain, and ovarian cancers) combined,
all Lynch cancers combined, breast cancer, prostate cancer, all
non-Lynch cancers combined, and all cancers combined. For colo-
rectal cancer, we censored each individual at the age of polypec-
tomy (except when it occurred within a year of the diagnosis of
colorectal cancer) and, for endometrial cancer, we censored each
woman at the age of hysterectomy (except when it occurred within
a year of the diagnosis of endometrial cancer).
Penetrance for carriers was estimated with a likelihood-based
approach as in Schaid et al. (25). Cumulative risks to age t years were
assumed to be logistic functions of t,
where estimates for the parameters a and b and the corresponding
standard errors and correlations were obtained by use of asymp-
totic maximum likelihood theory. A 95% confidence interval (CI)
for the cumulative risk to any age t was obtained by simulation.
The hazard ratio was estimated with a likelihood-based approach
that used a model in which the age-specific hazard for a mutation
carrier developing any of the above classes of cancer was assumed
to be the estimated hazard ratio times the sex-, country-, and age-
specific population incidence for the appropriate cancer group.
Average age-specific population incidences in 1998–2002 for each
country were obtained from Cancer Incidence in Five Continents (26).
Hazard ratios were estimated for each cancer group, each sex, and
each age category (as decades of age or as <50 vs ≥50 years), type of
mutation (point mutations, small insertions or deletions, and large
rearrangements), and ascertainment type (population-based vs clin-
ic-based). More than 90% of families were white, making any com-
parison in risks with non-white populations underpowered.
For both the penetrance and the hazard ratios analyses, we cor-
rected for ascertainment by conditioning the likelihood for each
pedigree, which was sampled independently of family cancer history,
on the proband’s MSH6 mutation status, cancer status, and age at
diagnosis. The likelihood for each clinic-based pedigree (which was
assumed to be ascertained because there was a family history of
cancer) and for each population-based pedigree (which was ascer-
tained because there was a family history of colorectal cancer) was
conditioned on the MSH6 mutation status of the proband and the
cancer status and age at censoring (if unaffected) or diagnosis (if af-
fected) of the proband and all relatives (27). For the analyses, we
included all first- and second-degree relatives for population-based
families who were ascertained irrespective of family history; for all
other families, all available relatives were included.
To gauge the number of mutation carriers in our study, we
estimated the number of carriers in the 131 families by using the
laws of Mendelian inheritance to calculate carrier probabilities for
every ungenotyped individual that was based on the known family
structure and mutation statuses of relatives. The estimated number
of carriers was calculated by summing the number of known car-
riers and the carrier probabilities of the ungenotyped relatives.
For each cancer group, 10-year cancer risks for carriers who
have not previously been diagnosed with the disease were esti-
mated as [R(t + 10) 2 R(t)]/[1 2 R(t)], where t is the carrier’s age in
years and R(t) and R(t + 10) are the relevant cumulative risks to ages
t and t + 10 years, respectively. Pedigree analyses were performed
196 Articles | JNCI Vol. 102, Issue 3 | February 3, 2010
with the pedigree analysis program MENDEL [Lange et al. (28)]
and other calculations in Stata (Stata Corp, College Station, TX)
version 10 (29).
Among the probands of the 113 families with an identified
mutation in MSH6, 31 carried a point mutation, 77 carried a
small insertion or deletion, and five carried a large insertion or
deletion. There were 74 distinct mutations of which, 22 were
observed across more than one family (range = two to six families)
(Supplementary Table 1, available online).
Among the 113 probands, 42 were sampled from population-
based sources that were independent of their family history or
cancer status, six were sampled from population-based sources
because of family history of cancer, and 65 were ascertained from
clinic-based sources. The personal cancer history of the probands
included 61 with colorectal cancer only, 33 with endometrial can-
cer only, 10 with colorectal and endometrial cancers, two with
ovarian cancer only, two with colorectal and ovarian cancers, one
with endometrial and ovarian cancers, one with small bowel can-
cer, and three with no cancer. Mean age at colorectal cancer diag-
nosis of affected probands was 52 years (SD = 10 years; range = 26–82
years). Mean age at endometrial cancer of affected probands was
51 years (SD = 9 years; range = 31–69 years).
The 48 population-based families included an average of 18.5
relatives per proband and contributed 15 742 person-years for an
estimated 346 mutation carriers; the 65 clinic-based families in-
cluded an average of 19.8 relatives per proband and contributed
35 544 person-years for an estimated 697 mutation carriers (Table 1).
In total (excluding probands), the families contain an estimated
1043 mutation carriers who contributed 51 286 person-years.
Definitive mutation status was known for all probands and for 278
relatives who were carriers and 247 who were noncarriers.
The colorectal cancer family history of the first- and second-
degree relatives of the 42 population-based probands who were
ascertained independent of their family cancer history was as fol-
lows: 18 (43%) had no affected relative, 14 (33%) had one affected
relative, seven (17%) had two affected relatives, and three (7%)
had three or more affected relatives. Thirty had a family cancer
history that did not meet the Amsterdam II criteria (30), and of the
remaining 12 (29%) who had a family cancer history meeting the
Amsterdam II criteria, four met the Amsterdam I criteria (30).
Among the relatives of all 48 population-based MSH6 mutation
probands, 37 had colorectal cancer (an average of 0.8 per family),
22 had endometrial cancer (an average of 0.5 per family), and 19
had another Lynch syndrome cancer (an average of 0.4 per family),
for a total of 78 Lynch syndrome cancers (an average of 1.6 per
family) (Table 2). Among the relatives of all 65 clinic-based fam-
ilies, 111 had colorectal cancer (an average of 1.7 per family), 49
had endometrial cancer (an average of 0.8 per family), and 28 had
another Lynch cancer (an average of 0.4 per family), for a total of
188 Lynch syndrome cancers (an average of 2.9 per family).
Table 3 and Figure 1 show that, by age 70 years, we estimate
that 22% (95% CI = 14% to 32%) of MSH6 mutation carriers who
were men would be diagnosed with colorectal cancer compared
with 10% (95% CI = 5% to 17%) of MSH6 mutation carriers who
were women. By age 80 years, we estimated that 44% (95%
CI = 28% to 62%) of MSH6 mutation carriers who were men
would be diagnosed with colorectal cancer, and this was greater
than the estimate of 20% (95% CI = 11% to 35%) of MSH6 muta-
tion carriers who were women. The 10-year risks of colorectal
cancer for MSH6 mutation carriers without a previous colorectal
cancer diagnosis at age 70 years were 28% (95% CI = 16% to 45%)
for men and 11% (95% CI = 4% to 23%) for women. The 10-year
risks at other ages were 6% (95% CI = 3% to 9%) at age 50 years
and 14% (95% CI = 8% to 22%) at age 60 years for men and 3%
(95% CI = 1% to 5%) at age 50 years and 5% (95% CI = 3% to
11%) at age 60 years for women (Table 4).
The two regions contributing the greatest number of popula-
tion-based families were Scotland (n = 21) and North America
(n = 27). We estimated that the cumulative risk to age 70 years for
Scottish men and women who were MSH6 mutation carriers was
33% (95% CI = 17% to 54%) and 15% (95% CI = 7% to 32%),
respectively, compared with the corresponding cumulative risks
for North American MSH6 mutation carriers of 18% (95%
CI = 8% to 36%) and 4% (95% CI = 1% to 21%), respectively.
These differences in cumulative risk by geographic region were
not, however, statistically significant (P = .4).
For MSH6 mutation carriers, the estimated risks for colorectal
cancer among men relative to those among men in the general
population (HR = 8.6, 95% CI = 5.5 to 13.4) were not statistically
significantly different from those among women (HR = 6.4, 95%
CI = 3.6 to 11.4; P = .4). When we combined men and women who
were MSH6 mutation carriers, the increased risk for colorectal
cancer, relative to that of the general population, over all ages was
Table 1. Data for the penetrance analysis by country and ascertainment method of recruitment of the proband
Population-based ascertainment Clinic-based ascertainment
No. of families Estimated No. of carriers*No. of families Estimated No. of carriers*
* Values were based on genetic relatedness to known MSH6 mutation carriers and noncarriers. The values do not include probands.
† Three Canadian and three US families had population-based ascertainment but were treated in analysis as ascertained on family history because of sampling
JNCI | Articles 197
statistically significantly elevated (HR = 7.6, 95% CI = 5.4 to 10.8;
P < .001). There was some evidence, although not statistically
significant (P = .15), that the risk for colorectal cancer among car-
riers younger than 50 years relative to similarly aged men and
women in the population (HR = 12.0, 95% CI = 6.4 to 22.8) was
higher than that for carriers 50 years or older relative to similarly
aged men and women in the population (HR = 6.5, 95% CI = 4.2 to
10.0). There was little statistical evidence that the increased risk to
carriers differed by mutation type (P > .3) or whether the proband
was ascertained from a population-based source independent of
their family history (HR = 7.8, 95% CI = 5.3 to 17.4) or from a
family cancer clinic (HR = 4.5, 95% CI = 2.3 to 9.0) (P for
difference = .5).
We estimated that 26% (95% CI = 18% to 36%) and 44% (95%
CI = 30% to 58%) of women would be diagnosed with endometrial
cancer by ages 70 and 80 years, respectively. The 10-year risk of
endometrial cancer for MSH6 mutation carriers without a previous
endometrial cancer diagnosis at age 70 years was 24% (95%
CI = 14% to 36%). The 10-year risks at other ages were 7% (95%
CI = 5% to 11%) at age 50 years and 14% (95% CI = 9% to 21%)
at age 60 years (Table 4). MSH6 mutation carriers who were
women had an endometrial cancer risk that was about 25 times
higher than women in the general population (HR = 25.5, 95%
CI = 16.8 to 38.7; P < .001).
MSH6 mutation carriers who were women had a cumulative
risk of at least one cancer of the ovary, stomach, small intestine,
Table 2. Characteristics of individuals with cancer known to be MSH6 mutation carriers and of individuals with an MSH6 mutation
carrier probability of 0.25 or higher (excluding probands) in MSH6 mutation-carrying families by ascertainment
Population-based families (n = 48)Clinic-based families (n = 65)
No. of diagnoses
y (range)No. of diagnoses
Other Lynch cancers
Brain 54 (32–65)
Total Lynch cancers
* Other cancers include lung (n = 28), breast (n = 25), skin (n = 13), prostate (n = 10), pancreas (n = 6), bladder (n = 6), testis (n = 5), liver (n = 4), thyroid (n = 4), pharynx
(n = 3), larynx (n = 2), bone (n = 2), myeloma (n = 2), leukemia (n = 5), lymphoma (n = 2), eye (n = 1), mouth (n = 1), biliary tree (n = 1), and unspecified (n = 14).
Table 3. Age-specific cumulative risk from birth (95% confidence intervals [CIs]) for cancer in MSH6 mutation carriers, for cancer by sex
Age-specific cumulative risk, % (95% CI)
50 y 60 y 70 y 80 y
Colorectal cancer Male
3 (1 to 7)
2 (1 to 5)
7 (4 to 11)
1 (0 to 6)
2 (1 to 5)
4 (2 to 9)
11 (7 to 16)
4 (2 to 9)
3 (1 to 6)
8 (5 to 15)
13 (9 to 19)
9 (5 to 14)
5 (2 to 9)
14 (9 to 20)
2 (0 to 8)
5 (3 to 9)
10 (6 to 18)
22 (16 to 30)
9 (5 to 16)
6 (3 to 12)
18 (13 to 27)
27 (21 to 35)
22 (14 to 32)
10 (5 to 17)
26 (18 to 36)
3 (1 to 14)
11 (6 to 19)
24 (16 to 37)
40 (32 to 52)
18 (11 to 29)
15 (9 to 23)
38 (28 to 51)
49 (41 to 60)
44 (28 to 62)
20 (11 to 35)
44 (30 to 58)
6 (1 to 25)
22 (12 to 38)
47 (32 to 66)
65 (53 to 78)
33 (19 to 51)
30 (17 to 47)
65 (51 to 80)
75 (65 to 86)
Other Lynch cancers*
Any Lynch cancer
* Other Lynch cancers include cancers of the kidney, stomach, ovary, small bowel, ureter, and brain.
198 Articles | JNCI Vol. 102, Issue 3 | February 3, 2010
kidney, ureter, or brain of 11% (95% CI = 6% to 19%) by age 70
years and 22% (95% CI = 12% to 38%) by age 80 years. They were
at six times the population risk of Lynch syndrome cancers other
than colorectal and endometrial cancers compared with the gen-
eral population (HR = 6.0, 95% CI = 3.4 to 10.7; P < .001). There
was no evidence for an increased risk of these cancers for MSH6
mutation carriers who were men (HR = 0.8, 95% CI = 0.1 to 8.8;
P = .9).
There was no evidence for an increased risk of breast cancer
(HR = 0.6, 95% CI = 0.2 to 1.6; P = .3), prostate cancer (HR = 0.2,
95% CI = 0.0 to 1.2; P = .08), or any non-Lynch syndrome cancers
among men or women. Overall, among those who carry an MSH6
mutation, we estimate that 24% (95% CI = 16% to 37%) of men
and 40% (95% CI = 32% to 52%) of women will be diagnosed with
any Lynch syndrome cancer by age 70 years and that these values
will increase to 47% (95% CI = 32% to 66%) of men and 65%
(95% CI = 53% to 78%) of women by age 80 years.
We have assembled, to our knowledge, the largest series of MSH6
mutation carrier families that has been used to estimate penetrance
to date. Among MSH6 mutation carriers, we estimated that ap-
proximately three in 10 men and one in 10 women will be diag-
nosed with colorectal cancer by age 70 years and that four in 10
men and two in 10 women will be diagnosed with colorectal cancer
by age 80 years. In contrast to our findings, a meta-analysis (18) of
Table 4. Risk of cancer in 10-year intervals for MSH6 mutation
carriers at ages 50, 60, and 70 years who have had no previous
diagnosis of the cancer (or group of cancers) at the beginning of
the 10-year period*
10-y cancer risk at age, % (95% CI)
50 y60 y 70 y
Colorectal cancer Male
6 (3 to 9)
3 (1 to 5)
7 (5 to 11) 14 (9 to 21)
6 (4 to 10) 15 (9 to 24)
Female 12 (9 to 17) 24 (17 to 33)
14 (8 to 22)
6 (3 to 11)
28 (16 to 45)
11 (4 to 23)
24 (14 to 36)
31 (17 to 48)
41 (29 to 55)
Any Lynch cancer† Male
* For example, a man with no previous colorectal cancer diagnosis at age 70
years has a 28% risk for development of a colorectal cancer by age 80 years.
† Any Lynch cancers include cancers of the colorectum, endometrium, kidney,
stomach, ovary, small bowel, ureter, and brain.
Figure 1. Age-specific cumulative risks from birth of Lynch syndrome
cancers for carriers of MSH6 mutations. CRC = colorectal cancer.
extracted data from just 10 families in two studies (17,20) predicted
that three in 10 carriers would be diagnosed with colorectal cancer
by age 70 years, with no difference between men and women, and
also observed no increase in colorectal cancer risk after age 70
years. We estimated that three in 10 MSH6 mutation carriers who
were women will be diagnosed with endometrial cancer by age 70
years and that four of the 10 carriers will be diagnosed by age 80
years, whereas the meta-analysis (18) estimated that approximately
three of the 10 carriers will be diagnosed with endometrial cancer
by age 70 years and five of the 10 carriers will be diagnosed by age
How do these estimates compare with those for mutations in
the other mismatch repair genes—MLH1, MSH2, and PMS2? A
meta-analysis (18) of three population-based studies (5,20,31) and
one clinic-based study (24) estimated that the risk of colorectal
cancer for MLH1 and MSH2 carriers was 53% for men and 33%
for women (compared with 22% and 10%, respectively, for MSH6
mutation carriers in this study), and the risk of endometrial cancer
was 44% (compared with 26% for MSH6 mutation carriers in this
study) with no substantial increases from age 70 years to age 80
years (compared with a 10-year colorectal cancer risk at age 70
years of 28% among carriers who were men and 11% among car-
riers who were women in this study, albeit with large confidence
intervals). For carriers of PMS2 mutations, the risk of colorectal
cancer to age 70 years was 20% among men and 15% among
women and the risk of endometrial cancer was 15% (32).
The major strengths of this study are the size and the statistical
methods that we used, which have resulted, to our knowledge, in
the most precise and unbiased estimates produced to date and,
therefore, of most clinical use of all published estimates. We
acknowledge that penetrance may depend on the MSH6 mutation,
the country in which the carrier lives, and other genetic and envi-
ronmental modifiers of risk; and thus, we have presented the av-
erage penetrance of all identified mutations across several countries.
There was no statistical evidence of heterogeneity of the pene-
trance by geographic region when comparing those of Scotland
with those of North America. A substantial proportion of the fam-
ilies for this analysis were ascertained because of a relative diag-
nosed with colorectal cancer at an early age; therefore, these
results may be more generalizable to MSH6 mutation carriers who
have a family history of early-onset disease.
A limitation of this study was that no haplotype analysis was
done for any of the mutations identified in more than one family,
and so it was not possible to conclude founder mutation status.
However, mutation c.651_652insT was identified in five of the
clinic-based families from the Netherlands; mutation c.1784delT
was identified in four clinic-based families from the Netherlands;
and mutation c.3939_3958dup19 was identified in three popula-
tion-based families from Scotland, which is consistent with a
common founder for each of these mutations.
The findings of this study indicate that the screening recommen-
dations for MSH6 mutation carriers may vary slightly from those
previously published for Lynch syndrome as a whole (Table 5). We
have shown that the risk for colorectal cancer and endometrial cancer
continued to increase between the ages of 70 and 80 years, although
the confidence intervals for the 10-year risks are large. Our data
suggest that screening for colorectal cancers should likely continue
JNCI | Articles 199
Table 5. Management for at-risk members of Lynch syndrome families with MSH6 mutation
recommendations for Lynch
syndrome as a whole
Levels of certainty* regarding
net benefit for Lynch syndrome
as a whole
MSH6 mutation carriers by
authors of this article
Cancer screening options
Colonoscopy Every 1–2 y beginning at age 20–25
y (age 30 y in MSH6 families) or
10 y younger than the youngest age
at diagnosis in the family, whichever
comes first (33); every 1–2 y starting
at age 20–25 y for men and age 30 y
for women (34); every 1–2 y starting
at ages 20–25 y (3)
Every year beginning at age 30–35 y
(33); every 1–2 y starting between
ages of 30 and 35 y (34)
Every year beginning at age 30–35 y
(33); every 1–2 y starting at age
30–35 y (34); every 1–2 y starting
between ages of 30 and 35 y (3)
Every 1–2 y beginning at age 25–35 y
(33) or beginning at age 50 y (34);
every 1–2 y starting between ages of
30 and 35 y if urinary tract cancer runs
in family (3)
“Could be offered periodically” (33);
every 1–2 y starting at age 30–35 y
if it occurs two or more times in
the family (34); every 1–2 y starting
between ages of 30 and 35 y if gastric
cancer runs in family or in countries
with high incidence of gastric cancer (3)
High† Every 1–2 y beginning at age
Endometrial samplingModerate (when combined with
transvaginal ultrasound) (35)
Every year beginning at age
Transvaginal ultrasound for
endometrial and ovarian
Poor Every year beginning at age
30–35 y. Role of serological
markers for ovarian cancer
screening is uncertain
Consider every 1–2 y beginning
at age 40 y
Urinalysis with cytologyPoor
GastroduodenoscopyPoor No evidence of increased risks
except by analogy to other
genes causing Lynch
Colorectal resection (segmental
vs subtotal colectomy vs
For at-risk persons without colorectal
cancer: generally not advised.
Discuss as alternative, with
preferences of well-informed patient
actively elicited. For persons with a
diagnosis of colorectal cancer or polyp
not resectable by colonoscopy, subtotal
colectomy favored with preferences of
the well-informed patient actively
elicited (33). The option of extensive
resection should be discussed with
patients younger than 50 y at colorectal
cancer diagnosis (3)
Discuss as option after childbearing
completed (33); may be an option for
women as it substantially reduces
site-specific cancers (3)
PoorNo change in recommendations
Hysterectomy or salpingo-
Moderate No change in recommendations
* The United States Preventative Services Task Force changed its grade definitions on the basis of a change in methods in May 2007 (36).
† Quality of evidence supports colon examination, but optimal frequency and initiation age have not been adequately addressed.
‡ In the cohort of relatives of the MSH6 mutation families, three (1.2%) of the 241 colorectal cancer diagnoses occurred at or before age 30 years, zero of the 129
endometrial cancer diagnoses occurred at or before age 30 years, and seven (5.4%) of the 129 endometrial cancer diagnoses were diagnosed between ages of
30 and 35 years.
into advanced years, being discontinued only when the risk of the
procedures outweighs the risk of development of a cancer. Careful
discussion between doctor and patient will be required to reach an
optimal decision on when or if that point has been reached.
For the management of gynecological cancers, the evidence sup-
porting the use of screening is moderate to poor (35) and, therefore,
underscores the consideration of risk-reducing bilateral salpingo-
oophorectomy and hysterectomy at a premorbid age. Endocervical
stenosis may render annual endometrial sampling increasingly diffi-
cult in many postmenopausal women. Cancer screening and preven-
tion in men and women with Lynch syndrome remain a subject in
flux, with much promise of noninvasive screening on the horizon for
some cancers including ovarian (37) and urothelial (38) cancers.
In conclusion, by aggregating data from 113 families that
contained approximately 1000 mutation carriers from five
countries and analyzing the data with statistical methods that
200 Articles | JNCI Vol. 102, Issue 3 | February 3, 2010
allow for conditioning on ascertainment, we have provided the
most precise cancer-specific estimates of penetrance to date for
carriers of MSH6 mutations. These results demonstrate that the
elevated risks for cancers in MSH6 mutation carriers differ by
sex of the carrier and continue into older age.
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Recruitment, data collection, and genetic testing for the Colon Cancer Family
Registry work were supported by the National Cancer Institute, National Institutes
of Health under Request for Applications #CA-95-011, and through cooperative
agreements with the members of the Colon Cancer Family Registry and principal
investigators. The Columbus-area Hereditary Non-Polyposis Colorectal Cancer
study performed by the Ohio State University Comprehensive Cancer Center was
supported by grants from the National Cancer Institute, National Institutes of
Health (R01-CA67941 and -CA16058). The work in Edinburgh was supported
by Cancer Research UK (C348/A8896); a center grant from CORE as part of the
Digestive Cancer Campaign (www.corecharity.org.uk); Medical Research Council
(G0000657-53203); and Scottish Executive Chief Scientist’s Office (K/OPR/2/2/
D333). National Cancer Institute (CA67941 and CA16058 to A.d.l.c. and H.H).
JNCI | Articles 201
University of Maastricht, Maastricht, the Netherlands (EBGG); Department
of Clinical Genetics, Leiden University Medical Centre, Leiden, the
Netherlands (AHJTV); Colon Cancer Genetics Group, Institute of Genetics
and Molecular Medicine, University of Edinburgh, Edinsburg, UK (NRC, RAB,
SMF, AT, MGD); MRC Human Genetics Unit, Western General Hospital,
Edinburgh, UK (NRC, RAB, SMF, AT, MGD); Human Cancer Genetics
Program, Department of Microbiology, Virology, Immunology, and Medical
Genetics (AdlC) and Division of Human Genetics, Department of Internal
Medicine (HH), The Ohio State University Comprehensive Cancer Center,
Columbus, OH; Division of Genetics and Population Health, Familial Cancer
Laboratory, Queensland Institute of Medical Research, Brisbane, Queensland,
Australia (DB, SA, JY, MDW); Imperial College London (JJ); Department
of Pathology, St Mark’s Hospital, Harrow (JJ); Department of Colorectal
Medicine and Genetics, Royal Melbourne Hospital, Victoria, Australia (FM);
Familial Cancer Centre, Department of Haematology and Medical Oncology,
PeterMacCallum Cancer Research Centre, Victoria, Australia (YA);
Department of Medicine (Royal Melbourne Hospital), The University of
Melbourne, Parkville, Victoria, Australia (IMW); Department of Genetics,
Royal Melbourne Hospital, Parkville, Victoria, Australia (IMW); School of
Child Health and Paediatrics, University of Western Australia, Perth,
Western Australia, Australia (JG); Department of Gastroenterology and
Hepatology, Middlemore Hospital, Auckland, New Zealand (SP); Familial
Cancer Unit, SA Pathology, Women’s and Children’s Hospital, North
Adelaide, South Australia, Australia (GS); Conjoint Gastroenterology
Laboratory, Royal Brisbane & Women’s Hospital Foundation, Clinical
Research Centre, Queensland Institute of Medical Research, Herston,
Queensland, Australia (BL); Department of Laboratory Medicine and
Pathology, Mayo Clinic, Rochester, MN (MB, SNT); Samuel Lunenfeld
Research Institute and Familial Gastrointestinal Cancer Registry, Mount
Sinai Hospital, University of Toronto, Toronto, ON, Canada (MA, SG);
Division of Epidemiology and Clinical Research, Department of Pediatrics,
University of Minnesota, Minneapolis, MN (JNP, RH); Department of
Medicine and Department of Community and Family Medicine Dartmouth
Medical School, Hanover, NH (JAB); Epidemiology Program, Cancer
Research Center of Hawaii, University of Hawaii, Honolulu, HI (LLM); Cancer
Prevention Program, Fred Hutchinson Cancer Research Center, Seattle, WA
(JP); Department of Gastroenterology and Hepatology, Leiden University
Medical Centre and The Netherlands Foundation for the Detection of
Hereditary Tumours, Leiden, the Netherlands (HFV).
The content of this manuscript does not necessarily reflect the views or pol-
icies of the National Cancer Institute or any of the collaborating centers in the
Cancer Family Registries nor does mention of trade names, commercial prod-
ucts, or organizations imply endorsement by the US Government or the Cancer
Family Registry. Authors had full responsibility for the design of the study, the
collection of the data, the analysis and interpretation of the data, the decision to
submit the manuscript for publication, and the writing of the manuscript.
The Dutch Lynch Syndrome Study Group comprises the following authors:
J. T. Wijnen (Department of Human Genetics, Leiden University Medical
Centre, Leiden, the Netherlands); M. G. E. M. Ausems (Department of
Clinical Genetics, Leiden University Medical Centre, Leiden, the Netherlands);
N. Hoogerbrugge (Department of Medical Genetics, University Medical
Centre Utrecht, Utrecht, the Netherlands); F. H. Menko (Department of
Clinical Genetics, University Medical Center Nijmegen, Nijmegen, the
Netherlands); T. A. M. van Os (Department of Clinical Genetics, Academic
Medical Center, Amsterdam, the Netherlands); R. H. Sijmons (Department
of Genetics, University Medical Centre Groningen, University of Groningen,
Groningen, the Netherlands).
We gratefully acknowledge the contributions of the study coordinators,
geneticists, analysts, and genetic counselors: Judi Maskiell, Pat Harmon,
Darshana Daftary, Terrilea Burnett, Allyson Templeton, Helen Chen, Sandy
Nigon, Mary Velthuizen, and Sarvaria Rose. Collaborating centers include
the Australian Colorectal Cancer Family Registry (UO1 CA097735), the
USC Familial Colorectal Neoplasia Collaborative Group (UO1 CA074799),
Mayo Clinic Cooperative Family Registry for Colon Cancer Studies (UO1
CA074800), Ontario Registry for Studies of Familial Colorectal Cancer (UO1
CA074783), Seattle Colorectal Cancer Family Registry (UO1 CA074794),
and the University of Hawaii Colorectal Cancer Family Registry (UO1
Affiliations of authors: Cancer Epidemiology Centre, Victorian Cancer
Registry, Carlton, Victoria, Australia (LB, GGG); Department of Medical
Genetics, Mayo Clinic, Rochester, MN (NML); Centre for Molecular,
Environmental, Genetic and Analytic Epidemiology, Melbourne School of
Population Health, The University of Melbourne, Parkville, Victoria, Australia
(JGD, DMW, JLH, MAJ); Department of Clinical Genetics, Erasmus Medical
Center, Rotterdam, the Netherlands (AW); Department of Clinical Genetics,