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Alberto Morán, Paloma Ortega, Carmen de Juan, Tamara Fernández-Marcelo, Cristina Frías, Andrés Sánchez-
Pernaute, Antonio José Torres, Eduardo Díaz-Rubio, Pilar Iniesta, Manuel Benito
REVIEW
Differential colorectal carcinogenesis: Molecular basis and
clinical relevance
Alberto Morán, Paloma Ortega, Carmen de Juan, Tamara
Fernández-Marcelo, Cristina Frías, Pilar Iniesta, Manuel
Benito, the second Department of Biochemistry and Molecular
Biology, School of Pharmacy, Complutense University, 28040-
Madrid, Spain
Andrés Sánchez-Pernaute, Antonio José Torres, Surgery
Service II, Clínico San Carlos Hospital, 28040-Madrid, Spain
Eduardo Díaz-Rubio, Oncology Service, Clínico San Carlos
Hospital, 28040-Madrid, Spain
Author contributions: Morán A, de Juan C, Frías C, Ortega P
and Fernández-Marcelo T performed the molecular analyses;
Sánchez-Pernaute A and Torres AJ assessed the clinical correlations;
Díaz-Rubio E was assessor of this work; Benito M directed and
coordinated this work; Benito M, Iniesta P and Morán A were
involved in writing the manuscript.
Supported by Grants from Ministerio de Sanidad y Consumo,
FIS PI080033; Fundación de Investigación Médica Mutua
Madrileña and RTICC RD06/0020/0021
Co rre spo nde nce to : Man uel Be nit o, PhD, the second
Department of Biochemistry and Molecular Biology, School of
Pharmacy, Complutense University, 28040-Madrid,
Spain. benito@farm.ucm.es
Telephone: +34-91-3941777 Fax: +34-91-3941779
Received: March 19, 2009 Revised: August 24, 2009
Accepted: August 31, 2009
Published online: March 15, 2010
Abstract
Colorectal cancer (CCR) is one of the most frequent
cancers in developed c ountr ies. It poses a ma jor
public health problem and there is renewed interest in
understanding the basic principles of the molecular biology
of colorectal cancer. It has been established that sporadic
CCRs can arise from at least two different carcinogenic
pathways. The traditional pathway, also called the
suppressor or chromosomal instability pathway, follows
the Fearon and Vogelstein model and shows mutation
in classical oncogenes and tumour suppressor genes,
such as
K-ras
, adenomatous polyposis coli, deleted in
colorectal cancer, or
p53
. Alterations in the Wnt pathway
are also very common in this type of tumour. The second
main colorectal carcinogenesis pathway is the mutator
pathway. This pathway is present in nearly 15% of all
cases of sporadic colorectal cancer. It is characterized by
the presence of mutations in the microsatellite sequences
caused by a defect in the DNA mismatch repair genes,
mostly in hMLH1 or hMSH2. These two pathways have
clear molecular differences, which will be reviewed in this
article, but they also present distinct histopathological
features. More strikingly, their clinical behaviours are
completely different, having the “mutator” tumours a
better outcome than the “suppressor” tumours.
© 2010 Baishideng. All rights reserved.
Key words: Colorectal cancer; Microsatellite instability;
Clinical outcome
Peer reviewer: Tzu-Chen Yen, PhD, Professor, Department of
Nuclear Medicine, Chang Gung Memorial Hospital, No.5, Fu-
Hsin St., Taoyuan 333, Taiwan, China
Morán A, Ortega P, de Juan C, Fernández-Marcelo T, Frías C,
Sánchez-Pernaute A, Torres AJ, Díaz-Rubio E, Iniesta P, Benito M.
Differential colorectal carcinogenesis: Molecular basis and clinical
relevance. World J Gastrointest Oncol
2010; 2(3): 151-158
Available from: URL: http://www.wjgnet.com/1948-5204/full/v2/
i3/151.htm DOI: http://dx.doi.org/10.4251/wjgo.v2.i3.151
INTRODUCTION
Colorectal cancer (CRC) is one of the most common
cancers in developed countries. The American Cancer
Society estimated that up to 153 760 new colorectal cancer
cases were diagnosed in USA during 2007 (the fourth
most common cancer for that period of time), with
52 180 associated deaths[1].
Online Submissions: http://www.wjgnet.com/1948-5204ofce
wjgo@wjgnet.com
doi:10.4251/wjgo.v2.i3.151
World J Gastrointest Oncol 2010 March 15; 2(3): 151-158
ISSN 1948-5204 (online)
© 2010 Baishideng. All rights reserved.
151 March 15, 2010
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Morán A
et al
. Differential colorectal carcinogenesis
Ferlay et al[2] estimated that colorectal cancer was the
second most common form of cancer in Europe during
2006 with 412,900 cancer diagnoses (12.9% of total
cancers) and 207,400 deaths (ranking second position).
These figures illustrate the clinical impact of colorectal
cancer. Due to the worldwide scale of the problem,
colorectal carcinogenesis is one of the most extensively
studied types of cancers.
CRC is traditionally divided into sporadic and familial
(hereditary) cases. Approximately, 75%-80% of colorectal
tumours have a sporadic origin. Of all patients, a high
proportion have one first to third-degree relative with
CRC. It is quite clear that even in sporadic CRC cases, the
descendants have a higher risk of suffering colorectal can-
cer. In this review, we will focus on sporadic CRC.
SPORADIC COLORECTAL CANCER:
DIFFERENTIAL CARCINOGENESIS,
DIFFERENT CLINICAL BEHAVIOUR
Currently, it is considered that there are two major path-
ways in colorectal carcinogenesis. One of them is called
the “canonical” (adenoma-carcinoma sequence) or “sup-
pressor” pathway and involves chromosomal instability
(CIN)[3]. It is characterized by allelic losses on chromo-
some 5q (APC), 17p (p53), and 18q (DCC/SMAD4).
The second pathway of colorectal carcinogenesis involves
microsatellite instability (MSI), and is called the “mutator”
pathway. The MSI pathway is present in approximately
15%-20% of sporadic CRCs[4].
Apart from their molecular differences, these two
pathways present different clinical behaviours and distinct
histopathological features, as will be discussed below.
SUPPRESSOR OR CANONICAL
PATHWAY
The “canonical” pathway is present in 80%-85% of
colorectal carcinomas and it is assumed to follow the
Fearon and Vogelstein approach. It is accepted that in
the majority of cases, carcinomas arise from pre-existing
adenomas. Fearon and Vogelstein[5] proposed a model of
colorectal carcinogenesis that correlates specic genetic
events with evolving tissue morphology. As is shown in
Figure 1, every step from the normal mucosa towards
the carcinoma involves specic and well-dened genetic
alterations. This linear model has evolved to a more
complex, comprehensive, and mechanistic approach[6].
However, in spite of the impact of new knowledge on
the Fearon and Vogelstein scheme, the model as such still
stands[7]. Alterations in tumour suppressor genes, such
as APC, p53, and DCC, and in oncogenes, such as K-ras,
are characteristic of this model and of the suppressor
pathway. CIN tumours are also characterized by a high
frequency of allelic imbalance (most commonly involving
chromosomal arms 5q, 8p, 17p, and 18q), chromosomal
amplications, and translocations[8].
APC
The adenomatous polyposis coli (APC, 5q21) gene contains
15 exons and it is mutated in 60% and 82% of colon and
rectal cancers, respectively[9]. Its best-known role is in the
Wnt pathway, where it is part of a multiprotein complex
that joins β-catenin and causes its phosphorylation, subse-
quent ubiquitination, and destruction in the proteosome.
This complex is mainly constituted by APC, axin, and
GSK3β. If this complex is disrupted, by multiple causes,
β-catenin is not directed towards degradation and is avail-
able to translocate to the nucleus and co-transactivate seve-
ral genes[10]. The list of Wnt target genes is quite long, but it
is important to note some cell cycle regulating genes (cyclin
D, c-Myc), and some genes related to tumour progression
(MMP-7, MMP-26). One of the main causes of disruption
of the multiprotein complex is mutations in APC. These
mutations interfere with binding to β-catenin and result in
the Wnt pathways becoming constitutively active.
However, APC also plays Wnt-independent roles,
whose alteration can also be related to carcinogenesis[11]. It
participates in cytoskeletal regulation, as it has been shown
to associate with microtubules and actin cytoskeleton,
suggesting that one role for APC may be in regulating
directed cell migration[12]. APC also has a role in mitosis.
APC has been reported at kinetochores, where it might
promote correct chromosomal alignment[13] and at centro-
somes, where it could inuence centrosome duplication[11].
It has been described that APC deficient cells cannot
properly detect chromosomal abnormalities during anap-
hase[14]. Therefore, loss of APC might interfere with the
correct regulation of mitosis and contribute to CIN[3].
Inactivation of APC has also been related to the promotion
of tumorigenesis, through loss of cell adhesion[15]. It has
been shown that a mutation in Apc in mice can decrease the
level of E-cadherin at the cell membrane[16]
Thus, we can consider that mutations in APC are a
frequent early event in the carcinogenesis of CCR and APC
is related to carcinogenesis at different levels: its activity in
the Wnt pathway, its relation with the cytoskeleton, its role
in chromosome segregation and, nally, its role in adhesion.
K-ras
K-ras is a proto-oncogene located at 12p12.1 that encodes
a 21-kDa GTP-binding protein. K-ras is frequently mu-
tated during the very early stages of colorectal cancer de-
velopment (35%-42% of colorectal cancers and advanced
adenomas present mutations on this proto-oncogene)[17].
When it is bound to GTP, the ras protein is active. This
protein is involved in many different processes. It activates
a large number of transduction signal pathways, among
them the mitogen-activated protein kinases (MAPK) path-
way. Recently, it has been demonstrated that mutant K-ras
promotes hyperplastic growth in the colonic epithelium
(signalling through MEK) and suppresses differentiation
in APC-mutant colon cancers[18]. It also regulates epithelial
cell polarity. During the development of CRC, epithelial
cells can loose their polarity and it has been described that
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an acquired mutation in K-ras reduces adherens junction-
mediated cell–cell contacts[19].
DCC
DCC (deleted in colorectal cancer) is located at 18q21.1 and
has been proposed as a tumour suppressor gene. About
70% of colorectal cancers show allelic losses in DCC[20];
some cancers had somatic mutations of this gene, and its
expression is often reduced in colorectal cancer tissues
and cell lines[21]. The DCC protein is a transmembrane
receptor of the Ig superfamily for netrins, factors involved
in axon guidance in the developing nervous system.
However, DCC has a role not only in axon guidance, but
in intracellular signalling. Chen et al[22] demonstrated that
the wild-type DCC, but not the mutant, induced apoptosis
and activated caspase-3, and that DCC expression induces
a rapid G2/M cell cycle arrest in some cell lines. DCC was
also shown to activate Rac-1 when netrin-1 is present[23];
thus it is implicated in actin organization and cell motility.
As reviewed by Mehlen and Fearon[21], transgenic mice
expressing a constitutive form of Rac-1 in the intestine
showed differentiation of the epithelium with accompanying
alterations in their apical actin. Hence, DCC-mediated Rac-1
activation might be important for epithelium differentiation.
p53
p53 is encoded by the TP53 gene located on 17p13.1. Its
expression is abnormal in more than 50% of human tu-
mours[24]. Mutation or loss of p53 usually occurs at the time
of the transition from adenoma to cancer in the Fearon
and Vogelstein sequence. As reviewed by Worthley[3], the
frequency of p53 abnormalities increases with the progres-
sion of the lesion. Thus alterations are found in 4%-26%
of adenomas, 50% of adenomas with invasive foci, and in
50%-75% of CRCs[3,17]. P53 protein induces G1 cell-cycle
arrest to facilitate DNA repair during replication of cells
exposed to environmental or oncogenic stress[20]. When
DNA damage is too great to be repaired, it can induce
apoptosis and this is considered a major pathway whereby
p53 exerts its tumour suppressor function[25].
MSI PATHWAY
Molecular alterations
The MSI, or mutator pathway, is present in approximately
15%-20% of sporadic CRCs. MSI tumours (also called
Replication ERor, RER+) are characterized by a huge
accumulation of mutations (mutation rates in these tumour
cells are 100- to 1000-fold more common compared to
normal cells[8]) in microsatellite sequences (High Micro-
satellite Instability, MSI-H). Microsatellites are short sequ-
ences repeated in tandem throughout the genome[26,27]. This
accumulation of frameshift mutations is caused by a primary
defect in the mismatch repair (MMR) genes (Figure 2).
There are at least seven genes in the MMR system: hMLH1,
hMLH3, hMSH2, hMSH3, hMSH6, hPMS1 and hPMS2[28].
When MMR proteins are functional, errors made by DNA
polymerase in microsatellite sequences during replication,
are repaired. The acquisition of thousands of mutations
characteristic of the MSI-H phenotype, requires the
inactivation of the MMR genes[4]. Germline mutations, or
epigenetic changes, in hMLH1 (mainly silencing caused by
methylation) and hMSH2 are the most common cause of
MSI-H in sporadic CRC (and in HNPCC, Hereditary Non
Polyposis Colorectal Cancer). hMSH6 mutations are less
frequent and alterations of the other MMR genes are very
rare[4]. These data enforce the idea that loss of hMLH1 and
hMSH2 is associated with complete inactivation of MMR,
whereas defects in other proteins cause only a partial MMR
deciency[28].
MSI-H sporadic colorectal cancers do not show big
cytogenetic abnormalities and are usually not aneuploid[29].
This type of tumour presents reduced frequency, or
absence, of mutation or allelic losses at the genes usually
altered in the “suppressor” pathway, APC, K-ras and p53,
and loss of heterozygosity at 5q, 17p, and 18q[30]. Instead,
mutations are described in microsatellite sequences present
in genes implicated in colorectal carcinogenesis, such
as TGF
β
RII[31] , IGF2R[ 32], BAX[33], MSH3[34] , MSH6[34],
caspase 5[35], APC[36],
β
-catenin[37], Tcf-4[38], axin[39], MMP-3[40],
E2F-4[41], BCL-10[42], cdx-2[43], and hRAD50[44] (See Table 1
for further information). Additionally, a number of normally
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Normal
epithelium
Micro
adenoma
Early
adenoma
Intermediate
adenoma
Late
adenoma Carcinoma Metastasis
Suppressor pathway
APC
mutation
Chromosome
5q LOH
K-ras
mutation
18q LOH,
DCC mutation
p53 mutation,
17p LOH
Other
alterations
Figure 1 Molecular alterations in the suppressor pathway.
functioning genes are silenced by methylation. Most sporadic
MSI-H cancers show the CpG island methylator phenotype,
characterised by widespread DNA hypermethylation[30].
Dening MSI-H tumours
International consensus criteria for classifying a tumour
as MSI-H were established in 1998[45]. A panel of five
microsatellite sequences was proposed for defining
the MSI-H tumour groups. The recommended panel
is composed of two mononucleotide repeats (BAT26
and A4725) and three dinucleotide repeats (D5S346,
D2S123, and D17S250). MSI-H tumours are dened as
having instability in two or more markers, whereas MSI-L
tumours are dened as having instability in one marker.
Microsatellite stability (MSS) is dened by no instability at
those ve loci. It is also important to stress that instability
is dened as a change of any length due to either insertion
or deletion of repeating units, in a microsatellite within a
tumour, when compared to normal tissue.
Clinical and histopathological characteristics
One of the most important and intriguing characteristics
of individuals with MSI-H tumours is that they have
distinct clinical and histopathological features. This is why
it is so important to determine a patient’s carcinogenic
pathway. Samowitz et al[46] reported that MSI-H was more
frequent in individuals with colorectal cancer diagnosed
before the age of 55 or over the age of 70, than in those
between 55 years and 70 years of age. However, these
data have not been confir med by other authors[47,48].
MSI-H tumours are located predominantly in the right-
sided colon[48-52] and have generally been reported more
frequently in women[46,53]. It has been proposed that the
analysis of MSI in CRCs might be helpful in predicting
the development of metachronous multiple colorectal
carcinomas[54].
MSI-H colorectal tumours typically present with a grea-
ter depth of invasion but with a lower overall stage[49,50,52].
MSI has also been associated with the presence of local
lymphocyte inltration and low frequency of distant metas-
tases[48,50,55]. In spite of its longer survival after surgical
resection (see below, in MSI-H and prognosis), MSI-H
carcinomas tend to be poorly differentiated[52]. Some studies
have demonstrated that MSI-H occurs more frequently
in mucinous-cell type tumours[53,56,57], but others have not
found any difference in histological cell type[49]. The absence
of dirty necrosis is also associated with MSI-H[50]. However,
as reviewed in Raut[52], it is not yet possible to use a single
pathological feature to diagnosis MSI-H. Greenson et al[50,58]
have recently developed a model that permits pathologists to
predict the likelihood of MSI using a combination of simple
histological and clinical data (mucinous differentiation,
lymphocyte inltration, and dirty necrosis).
MSI-H and prognosis
Many authors have reported a better outcome for MSI-H
tumours (whether sporadic or inherited) than those with
MSI-L or MSS tumours[46,47,59-62], though others have
not[63,64]. The prognostic advantage conferred by the
presence of high instability has been shown to be most
evident in stage Ⅱ and Ⅲ disease[62]. Individuals with
distant metastases present (stage Ⅳ) showing MSI-H
in the TGF-
β
R
Ⅱ
gene (transforming growth factor-β
receptor Ⅱ) had improved prognosis as compared with
those with native TGF-βRⅡ[46]. Moreover, MSI status
is considered to be predictive of a favourable outcome,
independent of tumour stage and of patient treatment[49].
Therefore, the MSI-H phenotype is associated with a good
prognosis, independently of the molecular biology (germ
line mutations or transcriptional silencing via hyperme-
thylation) provoking it[52]. In the short term, therapeutic
decisions might be taken in MSI-H patients considering
this differential prognosis. For example, Benatti et al[62]
demonstrated that 5-FU-based chemotherapy does not
seem to provide survival benefits among patients with
MSI-H tumours, so the use of 5-FU in patients with
MSI-H tumours should be limited to avoid harmful side
effects of unnecessary chemotherapeutic regimens
Classication of colorectal cancer by MSI status might
also have prognostic value in patients undergoing curative
surgery, as suggested by Banerjea[65] . MSI-H cancers
display enhanced immunogenic properties and this might
contribute to their better prognosis.
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hMLH1 hMSH2
hPMS1
hPMS2 hMLH3
hMSH6 hMSH3
hMLH1 hMSH2
hPMS1
hPMS2 hMLH3
hMSH6 hMSH3
DNA mismatch error
(base-base mismatch,
insertion, deletion
mismatch)
loop
DNA repaired Loss of function
Thousands of frameshift
mutations in coding and
non-coding
microsatellite sequences
Figure 2 Origin of the high microsatellite instability phenotype.
MSI-H VS MSI-L
As mentioned above, MSI-L tumours (also called mild
mutator phenotype) are defined as having instability
in one marker out of the five consensus microsatellite
sequences (as defined by Boland in 1998[45]). However,
not everybody denes MSI-L with the same criteria. The
distinction between MSI-H and MSI-L depends on both
the type and the number of microsatellites analyzed. For
example, mononucleotide markers, such as BAT26 and
BAT40, are relatively specic for MSI-H cancers[8]. This is
the reason why some groups use specic markers, such as
MYCL, for dening MSI-L tumours.
MSI-L tumours have been considered by some authors
to be halfway between MSI-H and MSS. However, MSI-L
colorectal tumours do not show clear differences in their
clinicopathological features when compared with the
classical “suppressor” tumours[66]. Yearsley et al[57] found
no difference between MSI-L vs MSS using clinical and
histological parameters such as percentage of mucin,
histological type, grade, and lymphoid host response.
Moreover, its molecular characteristics are more similar to
those from MSS than MSI-H tumours (reviewed in[8]). For
example, it has been described that LOH at 1p32, 2p16,
7q31, 8p12-22, and 17q11 is more frequent in MSI-L
than in MSI-H[66-68] and that K-ras mutations occur more
frequently in MSI-L carcinomas than in MSI-H colorectal
tumours, with no difference in frequency between MSS
and MSS-L cancers, by some authors[66,68]. The rate of
K-ras mutation is higher in the MSI-L group than in the
stable cancers[69]. Analysis of mutations in MSI-H target
genes revealed that they are absent in MSI-L tumours[4].
Some authors have even wondered about the real exist-
ence of the MSI-L group of tumours[70]. However, Jass
and others defended the notion that MSI-L is a separate
group of tumours, arguing that when a panel of sensitive
markers is used, approximately 8% of sporadic colorectal
cancers can be classied as MSI-L[69,71]. Others authors have
demonstrated the existence of specic markers for MSI-L,
such as MYCL and D2S123, which are mutated at a higher
rate outside the MSI-H subset[66].
In conclusion, we can consider that MSI-L CRCs are
indistinguishable from MSS using most clinicopathological
parameters. However, these tumours can be validated as
a distinct molecular phenotypic category, as they present
molecular alterations different from MSI-H and MSS
(reviewed in reference [4]).
SPORADIC MSI-H TUMOURS VS HNPCC
HNPCC (Lynch syndrome) constitutes approximately
2%-4% of all CRC cases[72]. The presence of MSI is also
a hallmark of this type of hereditary cancer. However,
the molecular mechanism causing MSI-H is different
in sporadic CRC than in HNPCC. In sporadic CRCs,
MSI-H is p rovoked mainly by epig enetic sile ncing
(hypermethylation) on hMLH1, whereas in HNPCC is
more frequent a germ line mutation in an MMR gene,
followed by a “second hit”.
Most of the molecular characteristics of sporadic
MSI-H tumours and HNPCCs are similar. However, some
small differences have been described recently. Oliveira
et al[73] demonstrated the presence of distinct patterns of
K-ras mutations in cancers according to hMLH1 methy-
lation status and germ line DNA MMR defects. BRAF
mutations (a serine/threonine kinase involved in the
RAS/RAF/MAPK pathway) in a specific hotspot site
have been more frequently detected in sporadic MSI-H
tumours than in HNPCCs[74].
There is no difference in overall survival amongst
MSI-H patients with HNPCC and those with sporadic
CRC[49].
CONCLUSION
Sporadic colorectal cancers can be classied in two clear-
ly different subtypes, according to the molecular events
that give rise to the tumour. The rst one is the so-called
canonical, CIN or suppressor pathway. It is the most fre-
quent pathway and it is characterized by mutation or de-
letion of K-ras, APC, DCC, and p53, among others genes.
The specic genetic events that occur during this pathway
have clear correlations with evolving tissue morphology.
The second pathway is the mutator or MSI-H pathway,
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Table 1 Genes with microsatellite instability in their coding
sequences. Adapted from reference [75].
Gene Function Coding repeat
ACTR
Ⅱ
Growth/differentiation factor
receptor
(A) 8
AIM2 IFN inducible (A) 10
AXIN-2 Wnt signaling (A) 6*2, (G) 7, (C) 6
BAX Proapoptotic factor (G) 8
BCL-10 Proapoptotic factor (A) 8
BLM Response to DNA damage (A) 9
Caspase-5 Proapoptotic factor (A) 10
CDX2 Homeobox transcription factor (G) 7
CHEK1 Response to DNA damage (A) 9
FAS Proapoptotic factor (T) 7
GRB-14 Growth factor bound protein (A) 9
hG4-1 Cell cycle (A) 8
IGFIIR Growth factor receptor (G) 8
KIAAO977 Homologue to mouse cordon bleu (T) 9
MBD-4 DNA glycosylase and methyl CpG
binding protein
(A) 10
MLH3 MMR (A) 9
MSH3 MMR (A) 8
MSH6 MMR (C) 8
NADH-UOB NADH ubiquinone oxidoreductase (T) 9
OGT O-linked GlcNAc transferase (T) 10
PTEN Cell cycle (A) 6*2
RAD-50 Response to DNA damage (A) 9
RHAMM Cell motility (A) 9
RIZ Cell cycle and apoptotic protein (A) 8, (A) 9
SEC63 ER membrane protein (A) 10, (A) 9
SLC23AI Nucleobase transporter (C) 9
TCF-4 Transcription factor (Wnt pathway) (A) 9
TGF
β
R
Ⅱ
Growth factor receptor (A) 10
WISP-3 Growth factor (Wnt pathway) (A) 9
which is less frequent. Its main molecular characteristic
is a huge accumulation of mutations in microsatellite
sequences throughout the genome, caused by primary
alteration in the MMR genes. As well as their important
molecular differences, the existence of these two path-
ways is relevant for their different phenotypes. MSI-H
tumours and CIN tumours have distinct clinical and his-
topathological features. Known molecular differences be-
tween the two groups of tumours are still not sufcient to
fully explain why MSI-H tumours have a better outcome;
its most intriguing characteristic. Recent studies are begin-
ning to shed light on this differential clinical behaviour,
but further work is required.
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High frequency of low-level microsatellite instability in early
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S- Editor Li LF L- Editor Stewart G E- Editor Yang C
