Current Genomics, 2008, 9, 420-435
1389-2029/08 $55.00+.00 ©2008 Bentham Science Publishers Ltd.
MUTYH Associated Polyposis (MAP)
M.L.M. Poulsen and M.L. Bisgaard*
Department of Cellular and Molecular Medicine, University of Copenhagen, 2200 Copenhagen N, Denmark
Abstract: MUTYH Associated Polyposis (MAP), a Polyposis predisposition caused by biallelic mutations in the Base Ex-
cision Repair (BER) gene MUTYH, confers a marked risk of colorectal cancer (CRC). The MAP phenotype is difficult to
distinguish from other hereditary CRC syndromes. Especially from Familial Adenomatous Polyposis (FAP) and to a
lesser extend Lynch Syndrome, which are caused by germline mutations in the APC and Mismatch Repair (MMR) genes,
Here we review research findings regarding MUTYH interactions, genotypic and phenotypic characteristics of MAP, as
well as surveillance and treatment of the disease. The applied papers, published between 1/1 2002- 1/2 2008, were found
The exact role of MUTYH in CRC tumorgenesis is still uncertain, although MAP tumors show distinct molecular features,
including somatic G:C>T:A transversions in the APC gene. Furthermore, cooperation between the BER and the MMR
systems exists, as MUTYH interacts with MMR gene-products. Possibly, monoallelic defects in both pathways are of sig-
nificance to CRC development.
Specific MUTYH variants are found to be characteristic in distinct ethnic populations, which could facilitate future genetic
screening. Knowledge concerning functional consequences of many MUTYH germline mutations remains sparse. Most
thoroughly investigated are the two most common MUTYH variants, Y179C and G396D, both generating dysfunctional
Phenotypic features of MAP include: development of 10-100 colorectal adenomas, debuting at 46-47 years, often CRC at
time of clinical diagnosis, and in some, development of extracolonic manifestations.
Received on: April 18, 2008 - Revised on: April 28, 2008 - Accepted on: May 4, 2008
Key Words: Colorectal cancer, MUTYH associated polyposis, The MUTYH gene, base excision repair, (Attenuated) familial
adenomatous polyposis, lynch syndrome.
cancer worldwide . In 35% of CRC patients, statistically
significant effects of hereditary factors have been found .
For some of these patients the genetic background is known;
major CRC syndromes being: Lynch Syndrome, Familial
Adenomatous Polyposis (FAP) and MUTYH Associated
Polyposis (MAP), which will be focused on in this review.
Fig. (1) shows a delimitation of the groups of patients, which
are referred to in this paper.
Lynch Syndrome is characterized by the development of
particularly CRC and endometrial cancer at a young age.
Lynch Syndrome is an autosomal dominant disease often
caused by germline mutations in one of the Mismatch Repair
(MMR) genes [3, 5-7]. The clinical and genetic features of
the syndrome have previously been thoroughly reviewed in
Colorectal Cancer (CRC) is the second most prevalent
*Address correspondence to this author at the Department of Cellular and
Molecular Medicine, University of Copenhagen, The Panum Institute 24.4,
Blegdamsvej 3, 2200 Copenhagen N, Denmark;
tous Polyposis (FAP), is caused by a germline mutation in
the APC gene, and confers a near 100% risk of developing
CRC. FAP has been shown to account for less than 0.1% of
all CRC cases . The characterization of the APC gene
and protein-product has been repeatedly reviewed, among
others in  and . Phenotypic characteristics of FAP
include: early development of more than 100 and up to thou-
sands of colorectal adenomas, as well as extracolonic mani-
festations such as gastric and duodenal adenomas, desmoid
tumors and congenital hypertrophy of the retinal pigment
epithelium (reviewed in [8, 13-16]). In FAP, genotype-pheno-
type correlations have been identified, specific APC gene
mutations being associated with particular manifestations
reviewed in  and . Of particular clinical interest is
the milder phenotypical FAP variant, Attenuated Familial
Adenomatous Polyposis (AFAP), which is associated with
APC mutations in the extreme ends of, or in the alternatively
spliced region of exon 9 [11, 18]. AFAP is distinguished
from FAP by the development of less than 100 colorectal
adenomas, fewer extracolonic manifestations and the later
development of CRC [11, 13-16, 19]. One study showed that
about 8% of registered FAP families present with an AFAP
Another autosomal dominant disease, Familial Adenoma-
MUTYH Associated Polyposis (MAP) Current Genomics, 2008, Vol. 9, No. 6 421
patients and their families is shown to reduce the develop-
ment of CRC and CRC-associated mortality markedly [5, 9,
10, 13, 16, 20]. For Lynch Syndrome patients, the recom-
mendation is colonoscopy from about 20-25 years of age, in
intervals of 1-3 years [5, 7, 9, 20]. The benefit of screening
for endometrial cancer and other cancers associated with
Lynch Syndrome is still controversial, and recommendations
should be adjusted according to the individual patient’s
wishes, family history and possibly genotype [7, 9, 20].
Prophylactic screening of Lynch Syndrome patients, FAP
reviewed in  and . Sigmoidoscopy is advised to FAP
patients commencing in the early teens, typically in intervals
of 1-3 years, according to the clinical manifestations [13, 15,
16]. Furthermore, individual assessment is especially neces-
sary in FAP families displaying a more severe phenotype
. Additionally, FAP patients should be offered endo-
scopy of the upper gastrointestinal tract from the age of
about 25-30 years, in intervals of 1-5 years, according to the
severity of duodenal Polyposis . Moreover, prophylactic
colectomy is often advisable for FAP patients. Especially in
patients with an early first appearance of the disease, the
surgical procedure recommended varies between the indi-
vidual FAP patients [13, 15, 16]. For AFAP patients, colo-
scopy in intervals of 2 years is advised starting from 18-20
years of age, due to the later CRC development and the typi-
Recommendations for FAP surveillance was recently
cally more distal location of adenomas in AFAP patients
compared to FAP patients [16, 19].
type, no germline mutations in the APC gene can be found
. Similarly, one study of patients with an AFAP-like
phenotype (3-100 adenomas), found that merely about 10%
of these patients had inherited germline APC mutations .
However, another study (N=59) showed that almost 70% of
patients with an AFAP-like phenotype (10-100 adenomas)
had a germline APC mutation .
In as many as 30% of patients with a FAP-like pheno-
gene regarding the development of the Polyposis predisposi-
tion syndrome MUTYH Associated Polyposis (MAP) was
discovered . Since then, many aspects of MAP have
been investigated, and the important question of how, these
new discoveries can be used in the genetic counseling and
screening of individuals at risk of developing MAP, now
stands to be answered.
In 2002, the significance of mutations in the MUTYH
cluding analysis of functional consequences and the outlin-
ing of specific ethnic allelic frequencies of MUTYH variants.
In addition, we review the clinical aspects of the syndrome
and introduce a new nomenclature for MUTYH germline
mutations, which is likely to replace the nomenclature,
which is currently used.
Here we review the main genetic aspects of MAP, in-
Fig. (1). Delimitation of the groups of patients.
synchronous occurrence of Polyposis. a gen
and will be referred to throughout the text.
On a clinical basis:
The following groups of patients are defined on the basis of both clinical and genetic characteristics,
Patients presenting with adenomas in the colon and/or rectum.
Patients presenting with carcinomas in the colon and/or rectum,
with or without previous/synchronous occurrence of Polyposis.
MAP patients: (OMIM 608456)
Polyposis patients with detected biallelic germline mutations in
the MUTYH gene.
On a mixture of clinical and genetic basis:
FAP patients: (OMIM 175100)
Polyposis patients presenting with > 100 adenomas in the colon
and/or rectum and – in this paper - with a detected germline
mutation in the APC gene.
AFAP patients: (OMIM 175100)
Polyposis patients presenting with < 100 adenomas in the colon
and/or rectum. (Possibly with a detected germline mutation in the
Lynch Syndrome patients
(Previously known as HNPCC (Hereditary Non-Polyposis Colorectal Cancer
patients): (OMIM: HNPCC1: 120435, HNPCC2: 609310)
Several guidelines for the clinical diagnosis of these patients exist
(e.g. The Amsterdam criteria I and II  and the Bethesda criteria
). Familial disposition for CRC, possibly with a detected
germline mutation in a Mismatch Repair (MMR) gene.
422 Current Genomics, 2008, Vol. 9, No. 6
Poulsen and Bisgaard
overview of existing findings regarding MAP. We hope to
provide perspective of the significance of MUTYH, as well
as of which issues regarding MAP call for future investiga-
We believe that this review provides a broad, up-to-date
PATHOGENESIS OF MAP: THE MUTYH GENE AND
BASE EXCISION REPAIR
Base Excision Repair
Repair (BER) system, which serves as an important part of
cells´ defense against oxidative damage to the DNA. The
BER system and the functional role of MUTYH have previ-
ously been reviewed in detail by [22-31].
The MUTYH gene product is part of the Base Excision
cies (ROS), which are produced during aerobic metabolism,
exposure to certain chemicals or radiation, constantly threat-
ens the integrity of cellular DNA. The oxidized base 7,8-
dihydroxy-8-oxoguanine (8-oxo-G) is one of the most stable
and mutagenic products of oxidative DNA damage. 8-oxo-G
is often mistakenly paired with adenine (A), resulting in the
appearance of Guanine:Cytosine > Thymidine:Adenine (G:C
> T:A) transversions at the next round of DNA replication,
as the detection of stable 8-oxo-G:A base-pairs is missed by
the replicative DNA polymerases [22-31].
Oxidative DNA damage, caused by reactive oxygen spe-
MUTYH and MTH1, which are central enzymes in the BER
pathway, function by specifically recognizing and facilitat-
ing the removal of 8-oxo-G [23-31]. The specific mechanism
of recognition of the DNA-damage-specific glycosylases is
characterized as “base-flipping”, involving the outwards
rotation of nucleotides from the DNA helix. This allows the
incorporated bases to be assessed by fitting into base-specific
pockets of the glycosylases [22, 23, 26, 29-32]. The repair
process at the damaged site is subsequently completed by the
synthesis and incorporation of newly replicated DNA, in-
volving several repair steps, which are facilitated by a se-
quence of DNA repair enzymes [23, 25, 26, 28-30]. The
MUTYH glycosylase acts as the third level of BER, as it
postreplicativly excises the misincorporated A opposite 8-
oxo-G [23-25, 29-31]. For this reason, defective MUTYH
function is associated with an increased frequency of G:C >
T:A transversions . Inactivation of MUTYH has accord-
ingly been associated with various cancer forms , includ-
ing lung cancer, gastric cancer, CRC [25, 33-36] and re-
cently also endometrial cancer .
The human DNA-damage-specific glycosylases OGG1,
both in vitro and in vivo, have demonstrated that the MU-
TYH glycosylase directly interacts with various proteins
involved in other DNA repair pathways (reviewed by 
A number of studies of the human MUTYH glycosylase,
genes in Polyposis patients without any significant findings
of association with Polyposis or CRC phenotypes. [21, 38-
41]. However, OGG1 variants have recently been demon-
strated to be significantly associated with a multiple ade-
noma phenotype  and the development of sporadic CRC
, although the latter association was of borderline sig-
nificance and should be further investigated . This re-
Several studies have also screened the OGG1 and MHT1
view focuses exclusively on the significance of MUTYH mu-
tations in relation to MAP and CRC.
THE MUTYH GENE
gene, located on the short arm of chromosome 1 (1p32.1-
p34.3). The gene consists of 16 exons and encodes a protein
of 535 amino acids, the MUTYH glycosylase. Characteriza-
tion of the MUTYH gene and functional variants has been
reviewed in [22-26, 29].
Exon 3 in MUTYH is alternatively spliced in various
ways, generating different MUTYH transcripts [25, 29, 44].
In accordance with HGVS nomenclature rules, the longest
MUTYH transcript existing (NM_012222.2 extended at the
5´of exon 3) will be used as coding DNA reference se-
quence, as outlined by Leiden Open Variation Database
(LOVD) at http://www.LOVD.nl/MUTYH . The use of
the longest existing MUTYH transcript as coding DNA refer-
ence sequence is predicted to replace the previous commonly
used MUTYH transcript (NM_001048171), although many
authors still refer to this. Also, experts in this field (J. Samp-
son, F. Hes and S. Aretz) have recently discussed the use of
MUTYH reference sequence. They agree that NM_012222.2
extended at 5´of exon 3 is the best option to use as reference
sequence in the future .
The MUTYH glycosylase is encoded by the MUTYH
differs from the one used in many previous papers. An over-
view of the new and old terms regarding some of the most
common MUTYH mutations mentioned in this paper can be
found in Table 1.
Consequently, the amino acid numbering in this paper
DEVELOPMENT OF COLORECTAL ADENOMAS
AND CRC TUMORGENESIS IN MAP
tumorgenesis due to the gatekeeper role of the APC tumor
suppressor gene, which is involved in many cellular proc-
esses. (Reviewed in  and .) The development of co-
lorectal adenomas is likely to be initiated by an APC gene
left dysfunctional as a result of germline or somatic muta-
Somatic mutations in the APC gene are important in CRC
ciated with a Polyposis predisposition by Al Tassan et al. in
2002 . Defects in the BER genes were suspected, when
11 tumors from 3 related Polyposis patients showed somatic
mutations in the APC gene, consistent with a defective BER
system, while no germline APC mutations were found .
Defects in the MUTYH gene were first shown to be asso-
dispose to the development of colorectal adenomas in par-
ticular, has not yet been fully determined. However, the
number of spontaneous somatic C:G > T:A transversions in
the APC gene is significantly greater in tumor cells with bial-
lelic MUTYH germline mutations compared to tumor cells
without MUTYH mutations [21, 38, 40, 46, 47].
The DNA sequence adjacent to the sites of G:C > T:A
transversions in the 3’ end of the APC gene appears to be of
significance to the specificity of the MUTYH glycosylase. A
significantly higher occurrence of GAA sites has repeatedly
been demonstrated 3’ to the G:C > T:A transversions, thus
creating stop codons, and resultantly a truncated APC pro-
The cause as to why, mutations in the MUTYH gene pre-
MUTYH Associated Polyposis (MAP) Current Genomics, 2008, Vol. 9, No. 6 423
tein. These results are seen even though the G:C > T:A
transversions theoretically could occur at any other G:C site
in the APC gene [21, 38, 48]. Also, in vitro experiments with
E. coli MutY have revealed a pronounced sequence prefer-
ence for MutY to GAA . However, the significance of
these findings and the question as to why GAA sites seem to
be prone to G:C > T:A transversions, remain unclear and call
for further investigations.
compared to other key tumorgenesis genes frequently in-
volved in other cancers , as well as the considerable ex-
posure to ROS in the gastrointestinal tract, could be part of
the explanation of why germline MUTYH mutations, and
Both the high number of GAA sites in the APC gene
subsequently somatic APC mutations, are associated with
development of particularly CRC .
both adenomas and carcinomas, taken from MAP patients
have been found [46, 50]. Distinct features of MAP tumors
include: C:G > T:A transversions in the APC gene and the
proto-oncogene K-Ras [46, 50]. Comparable with somatic
APC mutations, statistically significant numbers of somatic
mutations in the K-Ras gene have been found in MAP tu-
mors, compared to tumors without MUTYH mutations [47,
50]. The described K-Ras mutations have all been identical
G > C transversions in codon 12, G12C [46, 47].
Characteristic molecular profiles of colorectal tumors,
Table 1. Overview of Nomenclature for MUTYH Germline Mutations
Nomenclature from Reference Sequence NM_ 001048171 Nomenclature from Reference Sequence NM_012222.2
(Extended at the 5’ end of exon 3)*
p. Y165C p.Y179C
p. G382D p. G396D
*The new nomenclature for MUTYH mutations is based on referral to the longest existing MUTYH transcript and were found at http://www.LOVD.nl/MUTYH
424 Current Genomics, 2008, Vol. 9, No. 6
Poulsen and Bisgaard
these, compared to carcinomas from Sporadic CRC, FAP or
Lynch Syndrome tumors , which can potentially be used
in classification of CRCs . These molecular characteris-
tics of MAP carcinomas include: low MSI (Microsatellite
instability), low frequencies of APC, ?-cantenin mutations
and LOH (Loss of Heterozygosity) of 18q, harboring the
SMAD4 gene, and the karyotype of tumor cells typically be-
ing near-diploid [46, 50].
Molecular features in MAP tumors are characteristic to
in Sporadic CRC has been only sparsely addressed, and with
contradictory outcomes. Halford et al. found no indications
of MUTYH involvement in Sporadic CRC . In contrast,
somatic mutations in the MUTYH gene have recently been
demonstrated in Sporadic CRC, indicating a role of the MU-
TYH gene in Sporadic CRC tumorgenesis .
The issue of a possible significance of the MUTYH gene
INTERACTION BETWEEN THE MUTYH GENE AND
THE MISMATCH REPAIR GENES
treplicativly correcting DNA errors, which occur during
DNA replication. The normal MMR function and characteri-
zation of defects in the MMR system have previously been
reviewed in [7, 29] and . Key proteins in the human
MMR system include MutL homologs (MTH1 and Pms2)
and MutS homologs (MSH2, MSH3, MSH6), the latter
group forming two heterodimeric complexes [7, 29, 52].
The Mismatch Repair (MMR) system functions pos-
systems exists, since in vitro experiments have shown that
MUTYH physically interacts with the MSH2/MSH6 het-
erodimeric complex via a hMSH6-binding domain [53, 54].
These two studies have further demonstrated, that the
MSH2/MSH6 complex stimulates the activity of the MU-
TYH glycosylase by enhancing the affinity of MUTYH for
8-oxo-G:A mismatched base pairs in the DNA [53, 54].
Presumably cooperation between the BER and the MMR
ence the interaction between MUTYH and MSH6, followed
by a massive decrease in activity of the MUTYH protein [54,
55]. Mutations in one or more of the genes involved in the
two systems possibly affect the repair of DNA damage
caused by 8-oxo-G. The importance of this in regard to CRC
tumorgenesis is still uncertain, although there have been in-
dications, that interaction between a defect MUTYH gene
and a defect MMR gene is of significance in regard to CRC
risk. In a study by Niessen et al. (N=210), a significantly
higher frequency of carriers of monoallelic MUTYH muta-
tions was found among CRC patients who also had a specific
MMR mutation (5/36=14%), in comparison to groups of
CRC patients with other MMR mutations (1/40= 2.5%) or
without MMR mutations (1/134 =0.7%) . In this study a
particularly strong association between monoallelic MUTYH
germline mutations and en missense variant of the MSH6
gene was found (4/20 = 20%) , consistent with the be-
fore mentioned interaction between the two corresponding
Several MUTYH germline mutations are shown to influ-
the BER and MMR pathways may be mutually exclusive,
In contrast, studies of CRC patients have indicated that
although none have found significant results [48, 57]. Fur-
thermore, Van Puijenbroek et al. found a remarkably mild
Polyposis phenotype in a patient both compound heterozy-
gote for MUTYH mutations, as well as being a carrier of a
MSH6 germline mutation, supporting this notion . How-
ever, these studies do not provide substantial data for any
conclusions, for which reason further investigations need to
be carried out.
ALLELIC FREQUENCIES OF MUTYH GERMLINE
MUTATIONS IN DIFFERING POPULATIONS
mutations in the MUTYH gene to date can be found at the
LOVD at http://www.LOVD.nl/MUTYH.
An overview of the most commonly identified germline
ferent populations, see Fig. (2). In European populations the
two missense mutations Y179C and G396D are most fre-
quently seen, and have solely been found in Caucasians. The
allelic frequencies of Y179C and G396D found among MAP
patients are much higher compared to those found in back-
ground populations, see Fig. (3).
Specific mutations in the MUTYH gene are found in dif-
be of significance with regard to the development of Poly-
posis, since neither has been found in Asian Polyposis pa-
tients or in the corresponding background populations [42,
43, 55, 59-61]. In studies of Korean and Japanese Polyposis
patients (N=97), 7.2% were biallelic carriers of other germ-
line mutations in the MUTYH gene [55, 61]. Other studies of
Korean and Singaporean Polyposis patients (N= 63) failed to
find any MUTYH mutations after screening of coding regions
in the entire gene, although these results may be biased due
to small sample size [43, 59, 60]. Characteristic mutations
found in Japanese Polyposis patients include the missense
mutation R245C and the splice-site mutation IVS10-2A>G,
neither of which were found in the corresponding back-
ground population .
In Asian populations, Y179C and G396D do not seem to
identified, all were homozygote for the missense mutation
E480X [38, 62, 63]. However, in a case-control study of In-
dian Polyposis patients (cases: N=120 and controls: N=100),
merely one case and one control were found to be heterozy-
gote for E480X, while no other MUTYH mutations were
found . These results suggest that MUTYH mutations are
unlikely to be of significant importance to development of
Polyposis among Indian individuals. Other MUTYH variants
found in noteworthy allelic frequencies in characteristic
populations are: c.1145delC (found in Italian MAP patients
in allelic frequencies of 0.07-0.11 [65, 66]), A473D (found in
Finnish Polyposis and CRC patients, in the latter group with
an allelic frequency of 0.01 ) and E383fsX451 (found in
Portuguese MAP patients with allelic frequencies of 0.15-
0.19 [68, 69]).
To date, five unrelated Indian MAP patients have been
apparent pathogenic importance have been found. The most
frequent of these are V22M, Q388H and S515F, the allelic
frequencies of which in healthy control groups are found to
be equivalent to those found among MAP patients [21, 39-
41, 48, 56, 67, 69-78].
In addition, other MUTYH polymorphisms without any
MUTYH Associated Polyposis (MAP) Current Genomics, 2008, Vol. 9, No. 6 425
Fig. (2). Mean Allelic Frequencies among Carriers of MUTYH Germline Mutations.
N= Number of biallelic and monoallelic MUTYH germline mutation carriers. Included are mutations which are believed to be of pathogenic significance, and which are
found with an allelic frequency of > 0,03 in mutation carriers from the respective countries.
The figure is based on data colleced from the following studies: Al-Tassan et al., 2002; Jones et al., 2002; Sieber et al., 2003; Sampson et al., 2003; Halford et al., 2004;
Fleischmann et al., 2004; Gismondi et al., 2004; Isidro et al., 2004; Venesio et al., 2004; Wang et al., 2004; Aceto et al., 2005; Kairupan et al., 2005; Miyaki et al., 2005;
Leite et al., 2005; Aretz et al., 2006; Kanter-Smoler et al., 2006; Niessen et al., 2006; Russel et al., 2006, Ajith Kumar et al., 2007.
Fig. (3). Mean Allelic Frequencies of p. Y179C and p. G396D in Background Populations.
N= Number of tested individuals. The individuals tested belong to control groups without Polyposis.
The figure is based on data colleced from the following studies : Al-Tassan et al., 2002; Enholm et al., 2003; Sieber et al., 2003; Croitoru et al., 2004; Isidro et al., 2004;
Leite et al., Miyaki et al., 2005; Peterlongo et al., 2005; Zhou et al., 2005; Aretz et al., 2006; Kairupan et al., 2005; Kanter-Smoler et al., 2006; Niessen et al., 2006;
Russel et al., 2006.
426 Current Genomics, 2008, Vol. 9, No. 6
FUNCTIONAL CONSEQUENCES OF SPECIFIC
GERMLINE MUTYH MUTATIONS
The two most common MUTYH mutations, the Y179C
and G396D, are situated in the catalytic and C terminal do-
mains of MUTYH, respectively. Both of these MUTYH
residues have important roles in the recognition of 8-oxo-G
in A:8-oxo-G mispairs [31, 32, 49, 79, 80]. Accordingly,
functional studies of murin variants corresponding to Y179C
and G396D have indicated compromised substrate recogni-
tion as a consequence of these mutations .
Poulsen and Bisgaard
the MUTYH, and is part of the pseudo-HhH (helix-hairpin-
helix) motif in the catalytic region of the MUTYH. This re-
gion is thought to promote the base-flipping mechanism in
substrate recognition, participate in maintaining stability
during this process, as well as being involved in DNA bind-
ing [30, 49, 79, 82] (thoroughly reviewed in ). Studies of
biallelic Y179C mutations in human cell lines illustrate, that
defective MUTYH function results from both significantly
reduced levels of MUTYH protein (Protein levels of 5-10%
compared to wild-type MUTYH levels) as well as from re-
duced binding and cleavage ability towards the mispaired
The Y179C mutation is located in the N-terminal end of
TYH, which is thought to be responsible for 8-oxo-G recog-
nition and binding, as well as mediating the base-flipping
mechanism [31, 32, 49, 79, 80]. Human cell lines with bial-
lelic G396D mutations show defective MUTYH function as
a result of the production of a dysfunctional protein. The
protein shows both reduced binding activity of mispaired
substrates (about 50% of the wild-type MUTYH activity), as
well as lower rates of repair, compared to the wild type MU-
TYH . However, the MUTYH protein levels in these cell
lines were found to be equivalent to the levels of wild type
protein, indicating that protein instability is not a conse-
quence of G396D mutations .
G396D is located in the C-terminal domain of the MU-
corresponding E. coli MutY variants, which have been shown
to severely compromise the activity of the glycosylase [21,
49]. In one study, the Y179C and G396D variants showed a
98% and a 86% reduction in adenine removal from a G:A
substrate, compared to the wild-type protein, respectively
. Likewise, both MutY variants exhibit significantly re-
duced rates of adenine removal compared to wild-type
MutY. The variants corresponding to G396D and Y179C,
showing a 6-fold and 80-fold slower rate, respectively .
Also, considerably reduced binding affinities for G and 8-
oxo-G substrates were observed in the cases of both variants
These results are consistent with previous studies of the
also been conducted, although none as comprehensive as for
Y179C or G396D, for which reason merely a short overview
will be given in the present review: R182C, R182H, R185Q
and G189E, all are located in the pseudo-HhH motif of the
MUTYH catalytic domain, are considered to induce func-
tional MUTYH changes comparable to those observed in cell
lines with Y179C variants [57, 69, 74, 75]. The missense
variants P405L and A473D, both located in the C-terminal
Functional studies of additional MUTYH mutations have
domain, are both supposed to have functional significance
close to or within the MSH6-binding domain of the MUTYH
gene, have been preformed: The variants R241W and V246F
have preserved their ability to physically interact with
MSH6, but both show reduced MUTYH function .
R245C, also located near the MSH6 binding domain, is
likewise assumed to compromise the interaction between the
MUTYH and MSH6 .
THE SIGNIFICANCE OF THE MUTYH GENE IN RE-
LATION TO THE DEVELOPMENT OF POLYPOSIS
Functional analyses of two MUTYH mutations, which lie
the MUTYH gene, more often than previously assumed, are
the disease causing factor in Polyposis patients. Sieber and
colleagues found, that an AFAP-like phenotype is more of-
ten caused by germline mutations in the MUTYH gene than
in the APC gene . Another study of patients with AFAP
phenotypes, found APC germline mutations and MUTYH
biallelic mutations in equal numbers of families . Con-
sistent with these results, a study of CRC patients by Enholm
et al. has suggested, that the contributions of germline muta-
tions in the APC gene and the MUTYH gene are fairly equal
Results from several studies indicate, that mutations in
found that 5-22% of the patients with 3-100 adenomas and
7.5-17% of those with over 100 adenomas had biallelic mu-
tations in the MUTYH gene [19, 40, 85]. Furthermore, sev-
eral studies have found that none of the patients, who had
biallelic germline MUTYH mutations (N=63), presented with
a phenotype consistent with severe classical FAP, the criteria
being: more than 1000 polyps or early-onset CRC (before
the age of 50 years), and the development of more than 100
polyps before the age of 35 years, respectively [40, 85, 86].
These results indicate that a higher proportion of AFAP-like
phenotypes are caused by MUTYH mutations compared to
In studies of Polyposis patients (N=995), it has been
CLINICAL FEATURES OF MAP
tics of MAP, using information gathered from different stud-
ies of MAP patients.
Table 2 provides an overview of phenotypic characteris-
MODE OF INHERITANCE
lic mutations in the MUTYH gene. The majority of family
histories of MAP patients were found to be consistent with a
recessive inheritance, typically with affected siblings, but
unaffected parents [19, 21, 38-40, 62, 65, 66, 68, 69, 74, 75,
85-87]. Furthermore, Russel et al. found no MUTYH germ-
line mutations among Polyposis patients, who were negative
for APC germline mutations, and had a family anamnesis
consistent with a dominant mode of inheritance . In con-
trast, other studies have found family histories appearing to
follow a dominant mode of inheritance among MAP patients
in about 15-30% of the studied cases [68, 69, 74, 78, 85].
However, it is possible, that a recessive trait as MAP, due to
a relatively high frequency of heterozygote mutation carriers
in some populations, can mimic dominant inheritance, dis-
MAP is an autosomal recessive disease, caused by bialle-
MUTYH Associated Polyposis (MAP) Current Genomics, 2008, Vol. 9, No. 6 427
playing a pseudo-dominant mode of inheritance, especially
in cases of parental consanguinity. On the other hand, some
have proposed a co-dominant model for mode of inheritance,
suggesting an increased CRC risk for monoallelic MUTYH
germline mutation carriers compared to non-carriers, as will
be discussed further [48, 57, 70, 71, 84, 88-92].
who were homozygote for germline MUTYH mutations, have
been found [57, 70, 71, 84, 90, 91] and Table 3. This indi-
cates that biallelic germline MUTYH mutations are highly
penetrant. Accordingly, in a case-control study of CRC pa-
tients (N=2,239), all homozygote MUTYH carriers (N=12)
developed CRC before the age of 60 years .
In studies of healthy controls, no unaffected individuals,
AGE AT TIME OF CLINICAL DIAGNOSIS OF MAP
MAP patients is typically around 47 years (range: 13-72
years, N=106) [19, 57, 62, 76, 77, 85-87] and Table 2.
The average age at time of clinical diagnosis among
higher among patients with biallelic MUTYH germline muta-
tions compared to Polyposis patients without MUTYH muta-
tions. This applies both to studied Polyposis patients with
<100 adenomas [57, 65, 74] as well as to Polyposis patients
with >100 adenomas, who are also negative for APC germ-
Characteristically, the age at time of clinical diagnosis is
line mutations [40, 93]. In one of these studies (N= 58) this
result was statistically significantly .
fication of MAP patients is complicated, as MAP patients
often seem to be sporadic cases with no family history of the
disease at clinical presentation. Consequently, most MAP
patients are diagnosed due to symptoms and not as a result of
prophylactic screening, unlike many FAP and AFAP patients
. In accordance to this, many MAP patients are also typi-
cally discovered at a later time in the course of their disease
than other groups of Polyposis patients. For example, this
can be illustrated by the higher proportion of MAP patients,
who have already developed CRC at the time of their clinical
diagnosis as compared to FAP patients (see later).
Because of the recessive mode of inheritance, the identi-
DEVELOPMENT OF ADENOMAS
regard to the number of adenomas are generally seen to be
more severe in MAP patients compared to the phenotypes of
AFAP patients, but milder compared to those of classic FAP
patients [40, 61, 68, 74, 85].
In several studies of Polyposis patients, the phenotypes in
100 adenomas (Table 2), which is a smaller number than
seen in the classic FAP phenotype. Several studies of Poly-
posis patients have all found the highest incidence of bialle-
Characteristically, MAP patients develop between 10-
Table 2. Clinical Features of Identified MAP Patients
Sieber et al.
Sampson et al.
Isidro et al.
Wang et al.
Nielsen et al.
Russell et al.
Number of MAP
Mean age at the
time of clinical
For Patients with
For Patients with
Number of colo-
43%: Median: 55
adenomas were tested)
In this table only studies in which the numbers of tested MAP patients are > 5 are included.
The tested individuals are all APC germline mutation negative. The individuals tested are either probands or call-up patients with colorectal adenomas.
428 Current Genomics, 2008, Vol. 9, No. 6
Poulsen and Bisgaard
lic MUTYH mutations in groups of patients with between 15-
100 adenomas [40, 57, 61, 69, 85]. In the applied studies, the
incidences of biallelic MUTYH mutations in the groups of
patients having 15-100 adenomas, were found to be between
16-47% (N=835). However, none of the results were statisti-
In a recent study of AFAP patients (N=140), comparing
the clinical features of patients with APC (N=93) and bialle-
lic MUTYH germline mutations (N=26), no significant dif-
ferences between the two groups were found . However,
this result might be biased due to the smaller sample size of
the MAP patients compared to the patients with germline
APC mutations. When compared to Polyposis patients with-
out mutations in neither the MUTYH nor the APC gene,
MAP patients seemed to develop the lowest number of ade-
nomas, although no statistically significant results have been
found [40, 77].
regardless of whether their occurrence is caused by germline
mutations in the MUTYH or in the APC gene [40, 65]. Like-
wise, microadenomas have been found in patients with both
genotypes [40, 46, 62].
The morphology of the adenomas appears to be similar
DEVELOPMENT OF CRC
germline MUTYH mutations were found in 0.4-1.9% of all
cases (Table 3). Based on these results, the contribution of
biallelic MUTYH mutations to CRC seems to correspond to,
In several studies of CRC patients (N=3,320), biallelic
Table 3. The Frequencies of Carriers of MUTYH Germline Mutations Y179C and G396D Among CRC Patients and Back-Ground
Enholm et al.
Croitoru et al.
et al. 2004
Wang et al.
et al. 2005
Webb et al.
Küry et al.
Canada UK USA USA UK France
0.5 % 2.3 % 2.2 % 2.3 % 1.7 % 2.1% 2.3%
Biallelic carriers 0.4 % 1.9 % 0.6 % 0.5 % 0.8 % 0.2% 0.1%
age of carriers
0.9% 4.2% 2.8% 2.8% 2.5% 2.2% 2.4%
0 1.7% 1.9% 0.8% 2.11% 1.8%
Biallelic carriers 0 0 0 0 0 0
In this table only studies in which the numbers of tested individuals are > 50, are included. *Based on data from studies by Al-Tassan et al., 2002 and Sieber et al., 2003.
MUTYH Associated Polyposis (MAP) Current Genomics, 2008, Vol. 9, No. 6 429
or even be greater than that of FAP, FAP accounting for less
than 0.1% of all CRC cases, as found by Bülow .
nificant association between biallelic germline mutations in
the MUTYH gene and the development of CRC, has been
determined [75, 92]. In one of these studies (N=2,239), MAP
patients were found to have a 93-fold increased risk of de-
veloping CRC compared to a group of unaffected controls
from the general population .
Among MAP patients, the average age of CRC onset is
found to be 47 years (range: 29-72 years) [19, 62, 68, 75, 85,
87]. The frequency of patients with a synchronous CRC at
time of diagnosis is greater among MAP patients compared
to among FAP patients [69, 74, 93]. These results comply
with the fact that FAP patients generally are diagnosed ear-
lier than MAP patients, facilitated by the dominant mode of
inheritance of FAP and the use of Polyposis Registers in
many countries. Therefore, the prophylactic treatment of
FAP prevents the development of CRC in a higher number
of patients. As both probands and call-ups were included in
the applied studies, and as none of the results were statisti-
cally significant, more specific studies examining only
probands are needed.
In two other studies of CRC patients (N= 2,268), a sig-
typical location of carcinoma in MAP patients. Over-
representation of both right and left sided CRC has been
demonstrated [19, 39, 46, 71, 74, 75, 87, 88]. Presumably,
the location of CRC among MAP patients should not be con-
sidered important, as the prognosis seems to be independent
of the CRC location .
ASSOCIATED CANCERS AND EXTRACOLONIC
The manifestation of other primary cancers than CRC or
other extracolonic manifestations are less frequent among
MAP patients compared to among FAP patients . Sev-
eral studies have failed to report other cancers than CRC or
any extracolonic features among the examined MAP patients
[38, 40, 57, 61, 65, 66, 69, 71, 93]. The methods of clinical
examination were not specified in the applied studies. For
this reason, bias could be suspected, as patient information is
often gathered from several different databases without as-
surance that all patients were systematically examined.
Conversely, several studies have described the occur-
rence of extracolonic features in MAP patients, mostly upper
gastrointestinal lesions [37, 40, 62, 63, 74, 75, 78, 84-87, 94-
96], see Table 4.
However, these results should be regarded with reserva-
tions, as the numbers of examined MAP patients in the ma-
jority of the studies were very small. In addition, bias could
result from a difference in the methods of investigation used
in the individual studies, as these are only sparsely describe
in most of the studies. Also, some of the reported extracolo-
nic manifestations were reported in very low frequencies
among the examined MAP patients. They are therefore more
likely to be present by chance, rather than being associated
with biallelic MUTYH mutations.
There have been many inconsistent results regarding the
tations are generally not a part of the characteristic MAP
The described findings suggest that extracolonic manifes-
phenotype, but can occur. However, further studies with
more systematic and thorough investigation of MAP patients
are needed to address this issue.
HETEROZYGOTE AND CRC RISK
At present, no conclusive evidence has been found, that
monoallelic carriers of MUTYH germline mutations have an
increased CRC risk compared to the general population.
However, as seen in Table 3, percentages of carriers of
monoallelic germline MUTYH mutations are generally larger
among CRC patients, than the same percentages among the
corresponding background populations. Furthermore, several
studies have shown a tendency for a slightly elevated CRC
risk [40, 41, 57, 62, 66, 70, 71, 85, 88, 90, 93, 97], especially
in those over 55 years of age [41, 89, 92, 98]. However, res-
ervations towards these studies should be taken, as results
from the mentioned studies have failed to be convincing,
with merely one study achieving a slight statistical signifi-
cance . Also, some of the mentioned studies have been
criticized for the statistical methods used [98, 99], and meta-
analyses of the different studies have found inconsistent re-
sults [89, 98].
A suggested explanatory model for a possible association
between monoallelic MUTYH mutations and a co-dominant
mode of inheritance of CRC, is LOH of chromosome 1p,
where the MUTYH gene in located, possibly representing an
early event in CRC tumorgenesis [48, 70]. According to this
model, loss of the wild-type MUTYH gene on 1p in monoal-
lelic MUTYH mutation carriers is likely to contribute to an
increased CRC risk, as 1p LOH has been found in tumors
from monoallelic MUTYH mutation carriers [48, 77]. In con-
trast, other studies that have investigated 1p LOH in tumors
from monoallelic MUTYH mutation carriers have failed to
find results of sufficient significance to support this theory
from 9 case-control studies of CRC patients (Cases: N=
2,707 and controls: N= 2,321), and were not able to demon-
strate a significant association between monoallelic carriers
of MUTYH germline mutations and the development of CRC
. Consequently, as it –in the worst of cases- can only be
a matter of a minimally increased CRC risk compared to the
risk of the general population, it seems unlikely, that the ten-
dency for an increased CRC risk in heterozygote individuals
is powerful enough to be of diagnostic or prophylactic im-
On the other hand, Peterlongo et al. combined results
tions in CRC tumorgenesis is still uncertain, but as men-
tioned earlier, interactions with other genes, for example a
MMR gene, are possibly of significance.
The exact role of monoallelic MUTYH germline muta-
have found frequencies of monoallelic MUTYH mutation
carriers that correspond fairly well to those of biallelic carri-
ers, see Table 5.
This indicates that monoallelic MUTYH germline muta-
tions may be associated with a Polyposis phenotype. How-
ever, as seen in Table 5, the reported frequencies of mono-
and biallelic carriers vary considerably among studies. This
is likely to be a result of differing inclusion criteria, as these
are not thoroughly described in all of the applied studies.
In addition, several large studies of Polyposis patients
430 Current Genomics, 2008, Vol. 9, No. 6
Poulsen and Bisgaard
The significance of monoallelic MUTYH mutations needs to
be assessed further in comparable studies on the subject.
GENETIC COUNSELING AND PROPHYLAXIS
at the time of clinical diagnosis, before prophylactic treat-
ment can be initiated. Genetic testing and counseling of indi-
viduals at risk of developing MAP, is essential for the future
prospect of MAP patients, so that prophylactic screening can
be initiated. In this context it is important that knowledge
about the disease and mode of inheritance is continuously
searched for and utilized for the organization of guidelines,
which we believe will assure the best treatment for these
Frequently, MAP patients have already developed CRC
DETERMINATION OF THE GENOTYPE
monly seen in MAP families, siblings to an affected individ-
ual have a 25% a priori risk of disease. Consequently, deter-
Based on the recessive mode of inheritance most com-
mination of the genotype is especially important in these
individuals [62, 75, 92]. In some MAP families, the mode of
inheritance is pseudo-dominant, i.e. appears to be dominant
although in reality recessive [19, 68, 74, 87].
In practice, it is important to search for germline muta-
tions in both the APC and the MUTYH gene. This applies to
both individuals having a familiar disposition for multiple
adenomas and/or CRC as well as in apparently sporadic
CRC cases, if the clinical presentation gives hints of a Poly-
posis syndrome. In cases with a positive family anamnesis,
the most probable mode of inheritance can guide the assess-
ment of which gene to start with, i.e. the APC or the MUTYH
gene when a dominant mode or recessive mode is seen, re-
populations makes it possible to target the MAP screening in
accordance with ethnic background, thereby making the
screening more efficient, when the background of the patient
is known [57, 64].
Furthermore, the characteristic mutations in specific
Table 4. Extracolonic Manifestations Reported in MAP Patients
Number of MAP Patients (with
Biallelic MUTYH Mutations)
Overall Percentage of MAP
Patients with Extracolonic
(Adenomas and/or cancer)
N= 154 13% [40, 62, 74, 75, 77,
85, 86, 87, 88, 94]
Gastric lesions (Fundic gland pol-
yps or stomach cancer)
N= 133 8% [62, 85, 86, 87, 88]
CHRPE (Congenital hypertrophy of
the retinal pigment epithelium)
N= 22 18% [40, 93]
Osteomas N=14 14% 
Desmiod cysts N=14 7% 
Oesophageal cancer N=16 6% 
Thyroid carcinoma N= 57 4% [85, 95]
Breast cancer N=22 (female MAP patients)*1
Dental cysts N=14 7% 
Tooth agenesis N=7 14% 
Lipoma N=56 4% 
Multiple sebaceous adenomas N=2 (case reports) 100% [63, 95]
Sebacous carcinoma N=1*2 (case reports) 100% 
Pilomatricomas N=2 (case reports) 100% 
Melanoma N=4 25% 
Basocellular carcinoma of the skin N=49 2% 
CNS carcinoma N=55 4% [77, 88]
Leukemia N=6 17% 
Uterus cancer N=49 2% 
*1 An additional case of breast cancer in a biallelic MUTYH mutation carrier was reported by Olschwang et al. 2007, however no information on sex proportions in the examined
MAP patients was reported .
*2 This Patient was found to have biallelic MUTYH mutations, although no colorectal adenomas were found at the age of 53 years old. However, one case of be early-onset CRC
(before 50 years of age) was seen in the patient’s family. This patient had both endometrial cancer as well as sebaceous carcinoma .
MUTYH Associated Polyposis (MAP) Current Genomics, 2008, Vol. 9, No. 6 431
found mutations in Caucasian MAP patients, an obvious
possibility would be to screen specifically for these in Cau-
casian individuals . A disadvantage of such a selective
screening is, that MAP patients, who are compound het-
erozygote for just one of these variants, or homozygote for
other MUTYH variants, would be missed [57, 77, 86, 100].
Eliason et al. demonstrated an increased clinical sensitivity
for the detection of MUYTH mutations in their study, when
all exons and intron-exon boundaries of the MUTYH gene
were screened, compared to the sole testing for Y179C and
G396D . Accordingly, all coding regions of the MU-
TYH gene should be screened in individuals found to be het-
erozygote for Y179C or G396D to establish their true genetic
status [85, 86, 100]. Recently, Piccioli et al. have designed
specific assays for detecting the 6 most frequently found
MUTYH mutations using a multiplex T-ARMS-PCR method
. This method has been shown to be both accurate and
inexpensive, and can furthermore be adapted according to
the specific frequencies of MUTYH mutations in different
population groups . In patients presenting with an
atypical MAP phenotype, i.e. <10 colorectal adenomas or
familial mismatch repair proficient CRCs, van Puijenbroek
et al. have proposed a prescreening method also considered
As Y179C and G396D at present are the most frequently
to be cost-effective . This method consists of the
screening of tumors for KRAS2 c.34G > T, a somatic muta-
tion in the KRAS2 gene shown to be more common in MAP
patients compared to sporadic CRC cases. This should be
followed by screening for population specific MUTYH muta-
tions in cases positive for the aforementioned KRAS2 muta-
The frequencies of Y179C and G396D in the general
population are low compared to the occurrence among MAP
patients (Fig. (2) and (3)), and for this reason, there is at pre-
sent no indications for MAP screening of the general popula-
tion [75, 84, 85]. However, genetic testing of spouses of
MUTYH mutation carriers to asses the genotype and corre-
sponding disease risk of offspring, has been recommended
PROPHYLAXIS AND TREATMENT
reviewed by Vasen et al. in . Here a surveillance proto-
col in accordance with the recommendations for AFAP pa-
tients is suggested . However, some recommend begin-
ning at the age of 20-25 years, which is later compared to
AFAP recommendations . The surveillance of MAP pa-
The prophylactic surveillance of MAP patients is recently
MUTYH Germline Mutations Among Polyposis Patients who are Negative for APC Germline Mutations
Sieber et al.
Sampson et al.
Isidro et al.
Wang et al.
Nielsen et al.
Russell et al.
Slová et al.
Kim et al.
UK UK Portugal USA
(3 to >100)
(At least 10)
(10 to >1000)
(4 to >500)
(3 to >100)
(10 to >100)
All Exons Exon 7 + 13 All Exons
Exon 7 + 13,
In this table only studies in which the numbers of tested individuals are > 50 are included. The tested individuals are all APC germline mutation negative. The individuals tested are
either probands or call-up patients with colorectal adenomas. *1 The groups of tested Polyposis patients included both patients with < and > 100 colorectal adenomas. The reported
number of adenomas in the groups in question are given in brackets. *2 The common mutations Y179C and G396D are found in exon 7 and 13, respectively.
432 Current Genomics, 2008, Vol. 9, No. 6
Poulsen and Bisgaard
tients should consist of colonoscopy in two-yearly intervals
as opposed to sigmoidoscopy in FAP patients, due to the
often more attenuated phenotype and distal polyp location of
MAP compared to FAP [16, 19]. Furthermore, upper gastro-
intestinal endoscopy starting from the age of 25-30 years is
advised in MAP patients , even though the question of
upper gastrointestinal endoscopy ought to be further investi-
gated in studies, more specifically researching extracolonic
manifestations in MAP patients.
Naturally, the outlined recommendations should be ad-
justed according to the number, size and degree of dysplasia
of the adenomas of the individual patient .
FAP patients, the prophylactic treatment of MAP patients
should as a starting point be aimed at colonoscopy with
polypectomy. It could however be appropriate to apply
colectomy in MAP patients developing a particularly large
number or advanced adenomas [16, 19, 68].
Since MAP patients typically develop less adenomas than
GENETIC COUNSELING OF HETEROZYGOTE
CARRIERS OF MUTYH GERMLINE MUTATIONS
surveillance in heterozygote carriers of MUTYH germline
mutations at the present time. However, we believe that rela-
tives at risk of developing MAP should be searched for on
the basis of family anamnesis, if MUTYH germline muta-
tions are discovered, in order for appropriate measures to be
made on this basis.
In our judgment, there is no indication for prophylactic
CONCLUSION AND FUTURE PERSPECTIVES
velopment of CRC is yet to be resolved. Biallelic germline
mutations in the MUTYH gene are found to be associated
with a markedly increased risk of developing Polyposis and
CRC. The interactions between MUTYH and the MMR sys-
tem could play a role in the CRC tumorgenesis in MAP pa-
The full extent of the significance of MUTYH in the de-
phenotypes of FAP, AFAP, Lynch syndrome and MAP. As-
pects regarding phenotypic differences between MAP pa-
tients and other Polyposis patients form the base of the rec-
ommendations for counseling and prophylactic treatment of
MAP patients, which is stated here. Germline mutations
found in the MUTYH gene have shown a great ethnic vari-
ability, and further knowledge about this could be used to
target the genetic screening of Polyposis patients towards
specific population groups. Genetic screening for germline
mutations in the MUTYH gene as well as in the APC gene
should be performed on equal terms, perhaps guided by the
most probable mode of inheritance. Prophylactic surveil-
lance of MAP patients could be colonoscopy with polypec-
tomy in mind from 20-25 years of age.
In the future, more MAP patients could be identified be-
fore developing CRC by establishing MAP registers and
finding call-up patients based on family anamnesis, as it is
currently done for FAP patients in many countries. In this
way the future prospects of MAP patients could be improved
At times, it can be difficult to distinguish between the
base using the following terms: MYH Associated Polyposis
/MUTYH Associated Polyposis /MutYH Associated Poly-
posis. The search was only for material published in English
and was made without time-limitation. All papers published
between 01/01 2002 and 01/02 2008. We also searched ref-
erence lists of relevant papers.
The applied papers were all found in the PubMed data-
A = Adenine
AFAP = Attenuated Familial Adenomatous Poly-
= Adenomatous Polyposis Coli
= Base Excision Repair
C = Cytosine
= Colorectal Cancer
= Familial Adenomatous Polyposis
G = Guanine
= Hereditary Non-Polyposis Colorectal
= Loss of Heterozygosity
= Leiden Open Variation Database
MAP = MUTYH Associated Polyposis
= Mismatch Repair
= Microsatellite Instability
MUTYH gene = MYH gene = MutY Human Homolog
= Reactive Oxygen Species
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