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doi:10.3748/wjg.v17.i3.290
World J Gastroenterol 2011 January 21; 17(3): 290-299
ISSN 1007-9327 (print) ISSN 2219-2840 (online)
© 2011 Baishideng. All rights reserved.
REVIEW
Genomic and genetic alterations influence the progression
of gastric cancer
Stefania Nobili, Lorenzo Bruno, Ida Landini, Cristina Napoli, Paolo Bechi, Francesco Tonelli, Carlos A Rubio,
Enrico Mini, Gabriella Nesi
Stefania Nobili, Ida Landini, Cristina Napoli, Enrico Mini,
Department of Preclinical and Clinical Pharmacology, University of Florence, Florence, 50139, Italy
Lorenzo Bruno, Paolo Bechi, Department of Critical Care Medicine and Surgery, University of Florence, Florence, 50134, Italy
Francesco Tonelli, Department of Clinical Physiopathology,
University of Florence, Florence, 50134, Italy
Carlos A Rubio, Department of Pathology, Karolinska Institute
and University Hospital, Stockholm, 17176, Sweden
Gabriella Nesi, Division of Pathological Anatomy, Department
of Critical Care Medicine and Surgery, University of Florence,
Florence, 50134, Italy
Author contributions: Nobili S, Bechi P, Tonelli F, Rubio CA,
Mini E and Nesi G conceived and designed the study; Bruno L,
Landini I and Napoli C acquired and analyzed the data; Nobili S
and Nesi G wrote the paper; Bechi P, Tonelli F, Rubio CA and Mini
E revised the paper critically for important intellectual content.
Supported by Ente Cassa di Risparmio di Firenze
Correspondence to: Gabriella Nesi, MD, PhD, Division of
Pathological Anatomy, Department of Critical Care Medicine and
Surgery, University of Florence, Viale G.B. Morgagni 85, Florence, 50134, Italy. gabriella.nesi@unifi.it
Telephone: +39-55-4478114 Fax: +39-55-4379868
Received: April 27, 2010
Revised: August 9, 2010
Accepted: August 16, 2010
Published online: January 21, 2011
In this review, we summarize the sometimes contradictory findings regarding those markers which influence
the progression of gastric adenocarcinoma.
© 2011 Baishideng. All rights reserved.
Key words: Gastric cancer; Gene alterations; Prognosis;
Molecular pathology
Peer reviewers: Dr. Thomas Wex, PhD, Clinic of Gastroenterology, Hepatology and Infectious Diseases, Otto-von-Guericke University Magdeburg, Leipziger Str. 44, Magdeburg, 39120, Germany;
Hai-Yong Han, PhD, MS, BS, Division of Clinical Translational
Research, The Translational Genomics Research Institute (TGen),
445 N. Fifth Street, Phoenix, AZ 85004, United States
Nobili S, Bruno L, Landini I, Napoli C, Bechi P, Tonelli F, Rubio CA, Mini E, Nesi G. Genomic and genetic alterations influence the progression of gastric cancer. World J Gastroenterol
2011; 17(3): 290-299 Available from: URL: http://www.wjgnet.com/1007-9327/full/v17/i3/290.htm DOI: http://dx.doi.
org/10.3748/wjg.v17.i3.290
INTRODUCTION
Gastric cancer is one of the leading causes of cancerrelated deaths worldwide, although the incidence has
gradually decreased in many Western countries[1]. Several
attempts to classify gastric cancer have been made over
the past decades. Most successful, and widely used, is the
classification by Lauren, which, by microscopic morphology alone, distinguishes two main cancer pathogeneses,
diffuse and intestinal subtypes, which clearly appear as
dissimilar clinical and epidemiological entities. Although
most of the genetic alterations that have been reported
are observed in both intestinal and diffuse gastric cancers, it has become apparent that these two tumor types
result from different genetic pathways[2] (Table 1).
Microsatellite instability and p53 mutation, reduced
Abstract
Gastric cancer is one of the leading causes of cancerrelated deaths worldwide, although the incidence has
gradually decreased in many Western countries. Two
main gastric cancer histotypes, intestinal and diffuse,
are recognised. Although most of the described genetic
alterations have been observed in both types, different
genetic pathways have been hypothesized. Genetic and
epigenetic events, including 1q loss of heterozygosity
(LOH), microsatellite instability and hypermethylation,
have mostly been reported in intestinal-type gastric
carcinoma and its precursor lesions, whereas 17p LOH,
mutation or loss of E-cadherin are more often implicated in the development of diffuse-type gastric cancer.
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Nobili S et al . Gene alterations as prognostic factors in gastric cancer
MSI-H gastric carcinomas follow a molecular pathway
of tumor progression, characterized by the presence of
multiple frameshift mutations affecting mononucleotide
tracts within genes involved in cancer-related molecular
networks which control cellular homeostasis at different
levels. MSI-related mutations occur in many genes at variable frequencies[4]. Genes regulating cell-cycle and apoptotic signaling are frequently targeted in MSI-H gastric
carcinomas and include TGFβ RII, IGFIIR, TCF4, RIZ,
BAX, CASPASE5, FAS, BCL10 and APAF1[8]. Moreover, genes involved in genomic integrity maintenance,
i.e. hMSH6, hMSH3, MED1, RAD50, BLM, ATR and
MRE11, are also frequently altered in MSI-H tumors[9].
Several studies indicate that, in most MSI-H gastric cancers, multiple target genes are simultaneously mutated
and multiple hits impact on different genes in the same
pathway[10]. In contrast, gastric carcinomas with MSS and
MSI-L exhibit predominant p53 mutations[7].
As compared with MSS or MSI-L, gastric carcinomas
with MSI-H show a significantly higher frequency of
antral location, intestinal subtype, a lower incidence of
lymph node metastasis and improved survival[8,11-15].
p27 expression, cyclin E overexpression and 6.0-kb transcripts of the c-met gene are involved in malignant transformation from precancerous lesions to intestinal-type
gastric cancer. In addition, DCC loss, APC mutations, 1q
loss of heterozygosity (LOH), p27 loss, reduced expression of tumor growth factor (TGF)-β type Ⅰ receptor and
HER2 gene amplification are frequently associated with
an advanced stage of intestinal-type gastric carcinoma. In
contrast, LOH at chromosome 17p (p53) and mutation or
loss of E-cadherin are more often implicated in the development of diffuse-type gastric cancer, while loss of p27
and gene amplification of K-sam and c-met lead to disease
progression and metastatic spread.
The two types of gastric carcinoma organize different patterns of interplay between neoplastic and stromal
cells through the growth factor/cytokine receptor system, which has a critical role in cell growth, apoptosis,
morphogenesis, angiogenesis and metastasis. Other genetic factors, such as DNA polymorphism and genetic
instability, may also be implicated in the two distinct
major genetic pathways of gastric carcinogenesis.
GENOMIC INSTABILITY
CIN
CIN is a feature of various tumors, including gastric cancer, commonly associated with chromosomal aberrations
responsible for major modifications of DNA content,
i.e. changes in chromosome copy number, and also highlevel LOH, gene deletions and/or amplifications[16,17]. All
these alterations may lead to oncogene activation and/or
tumor suppressor gene inactivation. As with other tumors,
aneuploidy is generally considered an unfavorable prognostic factor[18-21], though contrasting results have been
reported[22-25].
High CIN levels have also been associated with a
shorter survival in gastric cancer patients[26] and high LOH
frequencies have been identified at several chromosome
arms, including 1p, 3p, 4p, 5q, 7p, 8p, 8q, 9p, 12p, 13q,
17p, 18q, 20q and 22q[27-29].
The allelotype of gastric carcinoma is similar to that
of colorectal and esophageal cancers, suggesting the presence of a common genetic pathway for tumor development. Some of these chromosomal segments include
genes which are strongly implicated in carcinogenesis,
such as the p53 gene on chromosome 17, DCC, DPC4
and SMAD2 genes on chromosome 18, and APC and
MCC genes on chromosome 5. Several studies have found
that tumors with LOH at chromosome 5q, 18q or 17p
had a poorer prognosis than tumors that did not show
LOH at these sites[30,31].
Two phenotypes of genomic instability are generally recognized in gastric cancer: the phenotype associated with
microsatellite instability (MSI) and that which is associated
with chromosomal instability (CIN). These phenotypes
are not necessarily independent and may even overlap in
some cases[3].
MSI
MSI is a common feature of gastric cancer due to a deficit
in the DNA mismatch repair system and derives from
the presence of spontaneous DNA replication errors in
simple repetitive sequences[4]. A standard panel of microsatellite markers, including mononucleotide (BAT26
and BAT25) and dinucleotide (D2S123, D5S346 and
D17S250) repeats, has been recommended and guidelines
for MSI testing (Bethesda Guidelines) have been drawn
up[5]. Using the reference panel, three levels of MSI can
be identified: high-level MSI (MSI-H), low-level MSI
(MSI-L) and microsatellite stable (MSS). Recently, it has
been established that mononucleotide repeats are instrumental in detecting MSI-H tumors because of their high
sensitivity and specificity, and MSI-L has been defined as
instability limited to dinucleotide loci[6]. After the adoption
of the Bethesda panel, MSI-H phenotype was reported in
a range of 5%-50% of all gastric carcinomas with significant differences in various ethnic groups. MSI-H appears
to be a phenotypical marker of an underlying cellular defect involving DNA mismatch repair (MMR). Functional
inactivation by mutations or epigenetic mechanisms of
MMR genes, including hMLH1 and hMSH2, is responsible for the MSI-H phenotype in gastric cancer. Abnormal
loss of protein expression of either hMLH1 or hMSH2
has been observed in MSI-H gastric carcinomas[7]. In particular, altered expression of hMLH1 has been associated
with gene inactivation by promoter hypermethylation.
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EPIGENETIC INSTABILITY
Epigenetic changes, such as aberrant methylation of CpG
islands in promoter regions, are commonly detected in
human cancers and can permanently inactivate tumorsuppressor genes and affect important pathways of cell
cycle regulation and proliferation. The methylation of CpG
islands may be considered a third molecular phenotype of
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Nobili S et al . Gene alterations as prognostic factors in gastric cancer
Table 1 Molecular genetic changes in gastric cancer
Intestinal
phenotype
(%)
Diffuse
phenotype
(%)
Local
progression
Distant
metastasis
Prognosis
Prolonged
survival
Ref.
Mutation, hypermethylation, reduced
expression
20-30
0-10
No
NA
Good
Yes
[8,11]
10-15
15-45
0
40-80
Yes
Yes
Yes
Yes
Poor
Poor
No
No
[57-59]
FHIT
NM23
Amplification/overexpression
Hemizygous deletion/
hypermethylation/loss of expression
Loss of protein expression (LOH, MSI)
Downregulation
35-65
3-25
20-80
30-70
Yes
Yes
Yes
Yes
Poor
Poor
VEGF
HIF-1α
Overexpression
Overexpression
65
25-60
35-45
45-60
Yes
NA
Poor
NA
COX2
Overexpression
60-70
30-70
Yes
Discordant
results
Yes
Yes
SPARC
Overexpression
70-80
25-55
Yes
p53
LOH/mutation/hypermethylation/
overexpression
Loss
Reduced expression
LOH/overexpression
Reduced expression
Reduced expression
Overexpression
Amplification
Amplification/overexpression
LOH/mutation/hypermethylation/
reduced expression
Overexpression
Overexpression
20-40
20-40
Discordant
results
Yes
Discordant
results
Poor
No
Discordant
results
No
Discordant
results
No
Yes
Yes
Yes
No
Yes
NA
Possible
Possible
Yes
Yes
No
Discordant
results
Abnormalities
Microsatellite
instability
Tyrosine kinases
HER2/neu
RUNX3
p21
p27
bcl2
BAX
pRb
c-myc
Cyclin E
E-cadherin
MUC1
PRL-3
Tumor-associated proteases
PAI-1
Overexpression
uPAR
Overexpression
uPA
Overexpression
60
50
0
50
Yes
Yes
No
NA
NA
Possible
Possible
Yes
Yes
30-60
30-40
15-65
25-60
Yes
Yes
40
10
60
45
15
0
5
50
10
5
15-20
[62-64]
[65,66]
[73,75]
[77-79]
[80-82]
[77,83,84]
No
[85-87]
No
correlation
Poor
Poor
Good
Poor
Poor
Poor
Poor
Poor
Poor
No
[88-91]
No
No
Yes
No
No
No
No
No
No
[92-94]
Poor
Poor
No
No
[95-97]
[98]
[99]
[1,92]
[101-104]
[92]
[107,108]
[65,106,110]
[112-114]
[115-117]
45-75
40-75
65
35-50
30-50
30
Yes
Yes
Yes
Yes
NA
NA
Poor
Poor
Poor
No
No
No
FHIT: Fragile histidine triad; LOH: Loss of heterozygosity; MSI: Microsatellite instability; VEGF: Vascular endothelial growth factor; HIF-1α: Hypoxia inducible factor-1α; COX2: Cyclooxygenase-2; SPARC: Secreted protein acidic and rich in cysteine; PRL-3: Phosphatase regenerating liver 3; PAI-1: Plasminogen activator inhibitor type Ⅰ; uPA: Urokinase-type plasminogen activator; u-PAR: u-PA receptor; NA: Not available.
As with colorectal cancer, the CpG island methylator
phenotype (CIMP), characterized by concurrent promoter hypermethylation of multiple genes, has also been
described in gastric cancer[45,46] and it has been shown to
correlate with hypermethylation of other known cancerrelated genes, such as p16, hMLH1 and THBS-1[45,47].
Furthermore, the CIMP status is associated with clinically useful information and patients with negative CIMP
methylation have significantly shorter survival than those
with high CIMP methylation[46,48].
gastric cancer and the tumor-related genes more commonly
methylated are APC, CDH1, MHL1, CDKN2A, CDKN2B
and RUNX3. It has also been widely reported that CDKN2A, CDH1 and MLH1 are more frequently inactivated
by promoter methylation rather than by mutations[32].
A series of individual methylated genes has been related to prognosis in gastric cancer. Methylation of tumorsuppressor genes, such as CDH1[33], DKK3[34], PTEN[35]
and MGMT[36], of putative tumor-suppressor genes, such
as TFPI2[37] and CACNA2D3[38], and of other tumor-related genes, such as PCDH10[39] and SOX2[40], has been associated with shorter disease-free and/or overall survival.
The combined use of APC and CDH1 methylation
markers has identified a subgroup of patients with worse
prognosis[41]. Conversely, methylation of single genes has
been associated with a better prognosis in some cases.
Patients showing methylation of APC[42], the M1 region
of MAL promoter[43] and cyclooxygenase-2 (COX2)[44]
showed prolonged survival, compared to patients without
methylation of these genes.
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ALTERATIONS OF GENES INVOLVED IN
MOLECULAR PATHWAYS
Genetic and genomic variations occurring in genes and
molecules that participate in proliferation, invasion and
metastasis (e.g. growth factors and their receptors, signal
transducers, cell-cycle and apoptosis regulators, cell adhesion molecules, DNA repair genes and matrix metallo-
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Nobili S et al . Gene alterations as prognostic factors in gastric cancer
tumors, including gastric cancer. The absence of FHIT
protein has been shown to correlate with higher tumor
stage and histological grade[64], as well as with poor overall
survival[65,66].
proteinases) may influence the prognosis of patients with
gastric cancer.
Tyrosine kinases
Amplification of some tyrosine kinases (c-met, K-sam
and HER2/neu) is associated with human gastric cancer
progression. Alternatively, spliced transcripts and enhanced protein expression levels for some of these tyrosine kinases are correlated with the clinical outcome of
gastric cancer patients[49].
The oncogene c-met, encoding for the hepatocyte
growth factor receptor, is preferentially amplified in
diffuse-type tumors and has been described to be well
correlated with stage and prognosis[50,51]. Overexpression
of c-met has also been shown to be associated with lower
survival probability[52,53].
K-sam oncogene, a member of the fibroblast growth
factor receptor family, is more frequently activated in
diffuse-type tumors[2]. Overexpression of K-sam occurs
in approximately 32% of diffuse-type gastric cancers, and
the prognosis of K-sam-positive patients is poorer than
that of K-sam-negative patients[54].
The HER2 protein (HER2/neu or ErbB-2) is a glycoprotein with tyrosine kinase activity, homologous to the
epidermal growth factor receptor. HER2 is codified by a
gene located on chromosome 17q21 and does not bind
to any known ligand. Some studies demonstrated that
overexpression of c-erbB2 is selectively found in intestinal
tumors and may serve as a prognostic marker for tumor
invasion and lymph node metastasis. Overexpression of
HER2 protein in gastric cancer has been reported to range
from 7.4% to 38%[55-57]. The prognostic value of HER2
expression and/or amplification has been widely investigated with controversial findings. Although most available
studies indicate that the overexpression of HER2 is an
independent prognostic factor associated with a shorter
disease-free[58] and overall survival[57-59], some studies failed
to confirm its prognostic role on multivariate analysis[51] or
to find a correlation between HER2 overexpression and
survival parameters[56,60]. Also associated with poor survival is the presence of HER2 amplification[61].
NM23
The NM23 gene maps to chromosome 17q21 and encodes the nucleoside diphosphate kinase A, a member
of the NDP kinase family. NM23 expression is reduced
in metastatic melanoma and breast cancer cell lines[67].
Transfection into cell lines affects invasion, motility, colonization, differentiation and liver metastasis[68]. Decreased
expression of NM23-H1, the human homologue, is found
in advanced stages of human cancer[69,70].
The expression of the putative metastasis-suppressor
gene NM23 in gastric carcinoma is controversial. In several studies, expression of NM23 has been shown to be
inversely correlated with the metastatic potential of gastric
cancer[71,72] and with prolonged overall survival[73]. The results of other studies, however, suggest that NM23 is not
a metastasis suppressor gene and does not show correlation with metastasis[74,75].
VEGF
VEGF is a pro-angiogenic factor, frequently overexpressed
in tumors. Mutations of p53, which under physiological
conditions downregulates VEGF, may be responsible for its
overexpression[76].
A correlation of the expression of VEGF with lymph
node and liver metastasis has been described[77] and patients with VEGF-positive tumors have a rather worse
prognosis than those with VEGF-negative tumors[78,79].
HIF-1α
The hypoxia inducible factor, HIF-1α, is a transcription
factor that plays an essential role in cellular and systemic
homeostatic responses to hypoxia. The prognostic role of
HIF-1α expression in gastric cancer patients is controversial: high levels have been associated with a shorter overall
survival[80], but also with no difference in survival parameters[81]. However, its upregulation (high HIF-1α mRNA
or protein levels) has been found to be positively correlated with VEGF[82] or p53[80] protein expression in gastric
cancer patients, and overall survival of patients with high
mRNA levels of HIF-1α and VEGF, as well as of HIF1α and p53, was shorter compared to patients with different features.
RUNX3
RUNX3, a gene that codifies for a member of the runt
domain-containing family of transcription factors, frequently shows loss of expression due to hemizygous deletion and hypermethylation in gastric cancer. This gene,
generally expressed in only 45%-50% of gastric cancer patients[62,63], positively regulates the expression of BIM and
p21, and negatively regulates vascular endothelial growth
factor (VEGF), thus affecting apoptosis, cell growth arrest and angiogenesis. The loss or substantial decrease of
RUNX3 protein expression in gastric cancer has been significantly associated with shorter survival[62,64].
COX2
COX2 is one of the key isoenzymes in the production of
prostaglandins, and is thought to be involved in carcinogenesis. Some studies indicate that COX2 may play a role
in the development of gastric cancer, and its overexpression is associated with nodal metastasis, tumor invasion
and differentiation, implicating a poor prognosis[77,83,84].
FHIT
The fragile histidine triad gene (FHIT) encodes a diadenosine 5’,5’’’-P1,P3-triphosphate hydrolase and is
generally inactivated by deletion or methylation in several
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SPARC
The secreted protein acidic and rich in cysteine (SPARC
or osteonectin) is a member of a family of matricellular
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Nobili S et al . Gene alterations as prognostic factors in gastric cancer
cer patients whether with high or low p27 expression[97].
p53, p21 and p27 have also been analyzed in combination,
confirming their role as prognostic markers[91].
proteins that modulates cell-matrix interactions and cell
function without participating in the structural scaffolding
of the extracellular matrix. Since SPARC alters membrane
permeability, cell shape, proliferation, migration and attachment, it may play a role in angiogenesis. It has been
reported that its overexpression correlates with distant
metastasis and poor prognosis[85-87]. It is not clear whether
SPARC overexpression is a useful marker in the prediction
of lymph node metastasis development[85].
BCL2
BCL2 and p53 are closely linked in the regulation of apoptosis. LOH at the BCL2 locus is frequently observed in gastric cancer. The overexpression of BCL2 may have a role in
the development of gastric cancers. It has been shown that
BCL2 overexpression reduces cellular proliferative activity
and correlates with a less aggressive biological behavior of
the tumor. The prognostic role of BCL2 on its own or in
association with p53 has not yet been elucidated[98].
p53
The p53 protein plays a fundamental role in cell growth
and division. The function of the p53 gene is more frequently altered due to LOH and mutation than to DNA
methylation. Mutations of p53 are present in about 40%
of early and advanced, well-differentiated gastric cancers[88]. A lower incidence of p53 mutations has been
shown in young patients compared to older patients[89].
p53 can be investigated by immunohistochemical techniques, bearing in mind that the half-life of the p53 mutant protein is prolonged. Cells carrying the p53 mutant
protein can be stained with antibodies against p53, whereas cells carrying normal p53 are negative. Sequencing of
the gene after screening can also be performed in order to
determine the mutation location within the gene[90].
Overexpression of p53 often occurs in the early stages
of intestinal-type tumors, and there is no significant difference between early and advanced cancers. In contrast,
p53 abnormalities are not often seen in the early stages of
diffuse-type tumors, but tend to occur as the disease progresses[91].
BAX
BAX gene encodes a protein belonging to the BCL family members. Negative BAX protein expression has been
associated with de-differentiation, lymph node metastasis
and shorter survival, suggesting that BAX status may play
a role in the development and differentiation of gastric
cancer and tumor progression[99].
pRb
pRb encodes a protein that is a negative regulator of the
cell cycle. Poor prognosis of gastric cancer patients with
low levels of pRb expression has been reported[92,100].
c-myc
c-myc gene encodes a multifunctional, nuclear phosphoprotein that plays a role in cell cycle progression, apoptosis
and cellular transformation. It functions as a transcription
factor that regulates transcription of specific target genes.
The c-myc protein has been shown to be significantly
enhanced in well-differentiated gastric cancer[101] and associated with a poor prognosis[102]. Although c-myc is a
short-lived protein in normal cells, its stability is increased
in transformed cells through several mechanisms. One of
these has recently been identified in the overexpression of
a human oncoprotein, the cancerous inhibitor of protein
phosphate 2A (CIP2A) that stabilizes c-myc[103]. Interestingly, the expression of CIP2A has been associated with
reduced overall survival in gastric cancer patients[104].
p21
p53 cell cycle regulatory function is mediated by different effectors. One of these is a cyclin-dependant kinase
inhibitor (CDK I), the p21 protein. The cell cycle check
points are controlled by a cascade of phosphorylation.
Protein kinases such as cyclin-dependent kinases are activated by cyclins and inhibited by CDK I, although p21
is up-regulated not only through a p53 pathway, but also
through a TGFβRII pathway.
Levels of p21 expression could indicate the absence
of a functional p53 protein in neoplastic cells. It has been
reported that the survival of gastric cancer patients with
p21-positive tumors is significantly longer than that of
patients with p21-negative tumors[92]. The expression of
p21 is usually assessed in combination with p53 status and
contributes to predicting the clinical outcome of gastric
cancer patients[93,94].
Cyclin E
Cyclin E overexpression correlates with invasiveness and
proliferation and may be a marker of tumor aggressiveness. Although somatic mutations of the cell cycle inhibitor p16MTSI are rare, its reduced expression is associated
with depth of invasion and metastatic potential in both
diffuse- and intestinal-type gastric carcinomas. However,
recent data show that the survival of gastric cancer patients with cyclin E-positive tumors is not significantly
shorter than that of negative patients[92].
p27
It has been suggested that the cyclin-dependent inhibitor
p27, which controls the transition from G1 to S in the cell
cycle, has prognostic relevance in gastric cancer. Reduced
p27 expression is detected in approximately 40%-50% of
gastric cancers[28]. Some studies have shown that tumors
with a low expression of p27 protein are poorly differentiated and at an advanced stage[95,96]. However, some authors
have found no difference in overall survival of gastric can-
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E-cadherin
Cell adhesion molecules are implicated in human carcinogenesis. Cadherin is a superfamily of calcium-mediated
membrane glycoproteins, forming one of the four classes
of adhesion molecules. E-cadherin, one of the members
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Nobili S et al . Gene alterations as prognostic factors in gastric cancer
central role in tumor invasion and metastasis. The positive
correlation of histological data with the urokinase-type
plasminogen activator (uPA) and the plasminogen activator inhibitor type Ⅰ (PAI-1) has been reported. Moreover, the independent prognostic impact of both uPA
and PAI-1 on the survival of gastric cancer patients has
been demonstrated. Elevated uPA and PAI-1 levels have
been shown to be associated with shorter survival[115,116].
A trend towards poor prognosis has also been observed
in patients with high expression of the u-PA receptor (uPAR)[113] and the uPA system may therefore be a target for
novel therapeutic agents.
The prognostic role of some uPA genotypes has recently been investigated and an association was demonstrated between the exon 6 C/T polymorphism with invasive phenotype, but not with susceptibility or survival[117].
of the trasmembrane glycoprotein family expressed by
epithelial tissues, not only acts as a cell adhesion molecule,
but also plays an important role in growth development
and carcinogenesis. The intact function of E-cadherin is
crucial for the establishment and maintenance of epithelial
tissue polarity and structural integrity. Around 25%-40%
of hereditary diffuse gastric cancers are caused by heterozygous E-cadherin. The inactivation of the second allele
occurs by mutation and methylation events, and this results
in the complete inactivation of the protein[105]. Reduced
expression of E-cadherin correlates with infiltrative and
metastatic ability in gastric cancer[33] and the gene encoding
E-cadherin, CDH1, was among the first to be considered
as an invasion suppressor gene. Patients with E-cadherinpositive gastric cancers showed statistically significant prolonged 3- and 5-year survival rates, compared to patients
with E-cadherin-negative tumors[33,106].
It has been shown that serum soluble E-cadherin is
increased in several non-neoplastic diseases and also in
various cancers, including gastric tumors. E-cadherin may
be a potentially useful prognostic marker and high levels
of soluble E-cadherin correlate with the depth of tumor
invasion, as well as inoperability[107]. In addition, levels
higher than 10 000 ng/mL predict a survival of less than 3
years in more than 90% of patients[108].
The Wnt-frizzled-β-catenin signaling pathway is frequently activated in gastric carcinoma (e.g. upregulation of
Wnt gene expression or of genes for Wnt ligand receptors,
upregulation of RAC1 and inactivation of APC), leading to
poor differentiation and increased tumor invasiveness[109].
CONCLUSION
Gastric carcinomas are histologically and genetically
heterogeneous and are influenced by gene-environment
interactions resulting in the activation of multiple molecular pathways. The molecular subtypes of gastric cancer
include three main groups of tumors characterized by
either the CIN, the MSI or the CIMP pathways. Currently,
it is not clear whether or in what way knowledge of these
subtypes of gastric carcinomas is of use in clinical practice, with regard to predicting specific pathways with mutational and regulatory alterations that may interfere with
targeted therapies.
MUC1
Mucins are high-molecular weight glycoproteins containing oligosaccharides. These glycoproteins constitute the
major components of the mucus that protects the gastric
epithelium. Overexpression of mucin 1 (MUC1) has been
linked to poor prognosis in gastric cancer patients[65,110].
It has been reported that MUC1 may accelerate tumor invasion by the impairment of E-cadherin[111]. The
combined expression of MUC1 and E-cadherin shows
that survival for gastric cancer patients with abnormal
E-cadherin/MUC-positive expression was shorter than
for patients with other expression patterns[106].
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PRL-3
The phosphatase regenerating liver 3 (PRL-3) gene encodes a protein belonging to a class of prenylated protein
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