Gynecologic Manifestations of Hereditary Nonpolyposis Colorectal Cancer

Gynecologic Manifestations of Hereditary Nonpolyposis Colorectal Cancer

ABSTRACT: Hereditary nonpolyposis colorectal cancer (HNPCC) is an autosomal dominant cancer susceptibility syndrome associated with inherited defects in the DNA mismatch repair system. HNPCC family members are at high risk for developing colorectal, endometrial, and ovarian cancers. Studies of HNPCC families have helped define the important role that mismatch repair genes play in the molecular pathogenesis of endometrial and ovarian cancers. This review will describe some of the important clinical and molecular features of HNPCC-related endometrial and ovarian cancer and describe how genetic susceptibility can be identified in patients with sporadic endometrial and ovarian cancers. It is important to identify patients with HNPCC, as families of mutation carriers may benefit from genetic counseling, testing, and intensified cancer surveillance.

Hereditary nonpolyposis colorectal
cancer (HNPCC) is an
autosomal dominant cancer
susceptibility syndrome associated
with inherited defects in the DNA mismatch
repair system. Initially described
by Warthin in 1913 as the
cancer family syndrome,[1] HNPCC
is characterized by genetic susceptibility
to multiple malignancies, most
commonly of the colon and endometrium
(Table 1).[2,3] HNPCC is
believed to account for approximately
1% to 5% of all colorectal cancers[4]
and an estimated 0.5% to 1.4% of all
endometrial cancers.[5,6] The clinical
features of HNPCC include earlyonset
cancers, synchronous and/or
metachronous malignancies, and a
nearly complete (80%) penetrance of
the disease. Lifetime risk for cancer
in patients with inherited DNA mismatch
repair mutations has been estimated
as being as high as 91% for
males and 69% for females.[7] As
shown in Table 2, the cumulative
incidence of colorectal, endometrial,
and ovarian cancer in HNPCC is significantly
higher than in the general

The majority (70%-80%) of
HNPCC cases result from germline
mutations in the DNA mismatch repair
genes MLH1 and MSH2.[8,9]
Germline mutations in other mismatch
repair genes MSH6, PMS1, PMS2 are
found less frequently.[8] Loss of the
normal DNA mismatch repair leads
to genomic instability and confers a
mutator phenotype.[10,11] The mutator
phenotype is an essential feature
of tumorigenesis. Mismatch repair-
deficient cells rapidly accumulate somatic
mutations[12] that can affect a
variety of target genes regulating cell
growth and/or apoptosis.

Mutations in DNA mismatch repair-
deficient cells are typically single-
base mismatches and insertion/
deletions that frequently occur within
repeated DNA sequences. Tumors deficient
in mismatch repair often exhibit
instability in microsatellite DNA
repeats. This tumor phenotype is
called microsatellite instability (MSI).
The MSI phenotype is observed in a
high proportion (80%-90%) of colorectal
cancers in patients with inherited
(germline) mutations in MLH1 or
MSH2.[13] Since endometrial and
ovarian cancer frequently occur in
HNPCC families,[3,14-17] it is not
surprising that defective mismatch
repair plays a significant role in
sporadic endometrial and ovarian

Clinical diagnosis of HNPCC relies
on family history, and multiple
criteria have been employed to identify
putative carriers of mismatch repair
gene defects (Table 3). The
criteria have been expanded over time
to include extracolonic malignancies
as well as other risk factors for genetic
disease such as synchronous or
metachronous tumors. Identification
of HNPCC is important because families
of mutation carriers may benefit
from genetic counseling, testing, and
intensified cancer surveillance.

This review will discuss the molecular
basis of HNPCC-related malignancies
and will specifically focus
on the clinical relevance of mismatch
repair deficiency in sporadic and inherited
forms of endometrial and ovarian

Molecular Biology of
Mismatch Repair

Mismatch repair genes function to
ensure fidelity of DNA replication in
cell division. Replication errors can
occur through mismatches produced
by physical or chemical alteration of
nucleotides, misincorporation of nu
cleotides during replication, and genetic
recombination events. There are
now seven mismatch repair genes that
have been investigated in cancers:
PMS2, and MLH3. Figure 1 illustrates
how these proteins normally function
as complexes to repair single-base
mismatches or insertion/deletion type
mutations. The fact that the majority
of MSI-positive tumors have MLH1
or MSH2 defects supports the unique
functionality of MLH1 and MSH2.
The MSH2/MSH6 and MSH2/MSH3
heterodimers function as sensors, recognizing
mismatched DNA, whereas
the MLH1/PMS2 heterodimer initiates

Studies of mismatch repair gene
knockout mice have provided evidence
for the importance of an intact
DNA repair system in protecting
against cancer. Colon tumors form in
MSH2 null (both alleles deleted) mice
and demonstrate MSI.[19] By contrast,
MSH6 null mice tend to develop
tumors later in life, and these
tumors do not exhibit MSI.[20] Partial
functional redundancy between the
MSH2/MSH6 heterodimer and the
MSH2/MSH3 heterodimer explains
the low level of MSI found in MSH3
and MSH6 mutants.[21]

Accumulation of point mutations
and insertion/deletion (frameshift)
mutations in repeated DNA sequences
is detectable as MSI. Tumors demonstrating
MSI (mismatch repair
deficiency) show different polymerase
chain reaction (PCR) products at multiple
microsatellite sequences when
compared to the normal (nontumor)
DNA from the same patient (Figure 2).
A consensus panel of five microsatellite
markers has been established
(D2S123, D5S346, D17S250, Bat 25,
and Bat 26)[13] to facilitate and standardize
identification of tumors that
demonstrate MSI.

Mechanisms of Cancer Formation
Mismatch repair deficiency contributes
to cancer formation through
two distinct pathways (Figure 3, upper
pathway). These pathways are
likely related to each other; however,
a well-defined molecular link between
the two mechanisms has yet to be
defined. In mismatch repair-deficient
endometrial cancers, tumor-suppressor
genes that contain coding sequence
repeats such as PTEN (phosphatase
and tensin homolog), BAX (BCL2-
associated X protein), and IGF2R (insulin-
like growth factor 2 receptor)
may preferentially acquire mutations
and ultimately lead to tumor formation.[
22-24] With the exception of
PTEN (which has been shown to be
mutated in approximately 85% of hereditary
endometrial cancers),[25]
mutations in tumor suppressors and
cell-cycle regulatory proteins in MSIpositive
endometrial cancers are infrequent.[

The alternative mechanism for how
loss of DNA repair contributes to tumorigenesis
(Figure 3, lower pathway)
is that cells deficient in mismatch repair
fail to activate apoptotic pathways
in spite of overwhelming DNA
damage.[27] Cell line studies provide
evidence for the role of mismatch repair
proteins in the cell death pathway.
MSH2 null mouse embryonic
fibroblasts do not undergo apoptosis
in response to the DNA-damaging
agent MNNG (N-methyl-N'-nitro-Nnitrosoguanidine),
and overexpression
of MSH2 or MLH1 can induce (rescue)
apoptosis in MSI-positive or
MSI-negative cells.[28] Tumor cell
selection may therefore be initiated
by a failure of defective mismatch
repair proteins (MLH1 and MSH2) to
stimulate existing apoptotic pathways.[

As noted, MSI in hereditary cancer
is associated with an underlying
defect in one of the DNA mismatch
repair genes. Sporadic (nonfamilial)
endometrial tumors, however, rarely
demonstrate mutations in these
genes.[29-32] In sporadic endometrial
cancers, it is much more common
for MLH1 to be inactivated epigenetically
through promoter hypermethylation.
An estimated 70% to 90% of
endometrial cancers with MSI demonstrate
aberrant methylation of the
MLH1 promoter.[33,34] Promoter
hypermethylation in endometrial cancer
is associated with loss of MLH1
expression.[35] The elevated cancer
risk associated with the presence of
both germline (HNPCC) coupled with
the frequent somatic (epigenetic methylation)
inactivation of the mismatch
repair genes (MLH1) highlights the
significance of these genes in tumorigenesis.

Endometrial CancerGenetic Susceptibility
Approximately 5% of all endometrial
cancers result from inherited
cancer susceptibility.[36] Of inherited
endometrial cancers, an estimated
0.5% to 1.4%[5,6] are HNPCC-related.
HNPCC is the best-understood
inherited endometrial cancer susceptibility
syndrome. Endometrial cancer
is the most frequent extracolonic
tumor in HNPCC,[2,3,17] and the cumulative
lifetime risk of endometrial
cancer in HNPCC families is high-
approximately 40% to 60%.[3,14]
Although the majority of germline
mutations in HNPCC families are in
MLH1 and MSH2,[8] families that
carry germline mutations in MSH6
appear to have a preponderance of
endometrial cancers regardless of
whether or not they meet strict (Amsterdam)
clinical criteria.[37,38] An
analysis of 20 families with 146 MSH6
mutation carriers demonstrated an
overall lower risk for all HNPCCrelated
tumors but a significantly
higher risk for endometrial cancer
compared to MLH1 and MSH2 mutation

Clinical criteria for diagnosing
HNPCC have broadened over time
(Table 3) to reflect the understanding
that there is genetic risk in patients
who do not meet strict (Amsterdam)
clinical diagnostic criteria. There are
at least three risk factors for having
germline (inherited) defects in one of
the mismatch repair genes. Genetic
susceptibility is found in patients who
develop endometrial cancer at a young
age (< 60 years old),[36,40] who
present with synchronous or metachronous
malignancies,[41] or whose
tumors demonstrate MSI without epigenetic
silencing of MLH1 (MLH1-
unmethylated tumors).[42]

Women who do not meet strict clinical
(Amsterdam) criteria for HNPCC
but have early-onset (< 60 years old)
disease appear to have increased familial
clustering of malignancies. In
a large phone survey of 455 women
with early-onset endometrial cancer
(20-54 years old) compared with over
3,000 age-matched controls, the odds
ratio for endometrial cancer in a firstdegree
relative was 2.8 (95% confidence
interval [CI] = 1.9-4.2), and the
odds ratio for colorectal cancer within
the same family was 1.9 (95% CI =
1.1-3.3).[40] Another study examined
291 early-onset (< 60 years old) endometrial
cancer cases with available
parental data. Nine kindreds (3.1%)
met clinical criteria for HNPCC, and
an additional 3% had familial clustering
of malignancies.[36]

Patients with double primary malignancies
of the colon and endometrium
are another subgroup at-risk for
inherited cancer susceptibility. In a
study of 40 unrelated women with
colorectal cancer and endometrial cancer,
7 patients had MLH1 or MSH2
mutations and 6 of the 7 had family
histories suggestive of HNPCC. The
relative risk of colorectal cancer in
first-degree relatives of patients who
carried germline mutations in MLH1
or MSH2 was 8.1 (95% CI = 3.5-
15.9) and the relative risk of endometrial
cancer was 23.8 (95% CI =
6.4-61.0). First-degree relatives of
patients with double primary malignancies
without MLH1 or MSH2 defects
were also at increased risk for
colorectal cancer or endometrial cancer,
with a relative risk of 2.8 (95%
CI = 1.7-4.5) and 5.4 (95% CI = 2.0-
11.7), respectively.[41] Another study
of women diagnosed with both colon
and endometrial cancer (N = 80) revealed
that the relative risk of colorectal
cancer before age 55 in
first-degree relatives of probands who
had both cancers before age 55 was
30.5 (95% CI = 18.8-46.6).[43]

In addition to clinical factors (early-
onset disease and double primary
malignancies), loss of mismatch repair
in endometrial tumors can be
helpful in identifying women with
genetic susceptibility. A molecular
phenotype (MSI-positive, MLH1-unmethylated)
has been identified that
appears to highlight carriers of germline
mismatch repair mutations. Women
with MSI-positive endometrial
cancer without MLH1 methylation
demonstrate familial clustering of
malignancies, develop cancer almost
10 years earlier,[42] and have an excess
of HNPCC-associated metachronous

Clinical Significance of
Mismatch Repair Deficiency

Identification of HNPCC patients
is important because family members
have been shown to benefit significantly
from enrollment in colorectal
cancer surveillance programs.[45]
Whether the loss of mismatch repair in
HNPCC-related or sporadic endometrial
cancers is related to tumor behavior
or overall survival, however, is
controversial. In HNPCC-related endometrial
cancers, no difference has
been seen in 5-year cumulative survival
(all stages) or in histologic subtype
compared to age- and stage-matched
sporadic endometrial cancers.[46]

In a small study (109 tumor samples)
that compared MSI-positive (N =
10 tumors with high-level MSI) to
MSI-negative sporadic endometrial
cancers, MSI positivity was associated
with higher tumor grade and poor
clinical outcome.[47] A larger retrospective
study of sporadic MSI-positive
and MSI-negative endometrial
cancers, however, found no difference
in 5-year survival, 5-year recurrencefree
survival, stage, grade, or histologic

Another retrospective case/control
study of 29 MSI-positive endometrial
cancer patients demonstrated statistically
significant improvement in 5-
year survival (77% vs 48%) in a cohort
of patients weighted heavily towards
advanced-stage disease (> 50% of the
patients had International Federation
of Gynecology and Obstetrics [FIGO]
stage III or IV disease).[49] This benefit
was seen in univariate and multivariate
analysis. An analysis of 70
MSI-positive vs 159 MSI-negative
endometrial cancers (81% completely
surgically staged) found that MSIpositive
tumors tend to present with
early-stage disease and have a less
aggressive histology.[50] There were
also no differences seen in recurrence
or survival, but the median follow-up
for both groups was only 24 months.

Overall, it is important to recognize
patients who may have inherited
susceptibility to endometrial cancer,
as family members will benefit from
colorectal surveillance and may similarly
benefit from gynecologic surveillance.
The relationship between
MSI and endometrial cancer biology
and overall survival in HNPCC-related
or sporadic endometrial cancer is
not yet fully understood. A larger analysis
including prospectively acquired
clinical data in surgically staged patients
with known molecular phenotypes
would be helpful to better
understand differences in clinical outcomes
in these patients.


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