Gastric carcinoma is the most common malignant cancer
in the Korean population (1) and one of the most frequent
cancers in the world (2). Cancer is caused by the accumulation
of genetic alterations such as the activation of oncogenes and
inactivation of tumor suppressor genes (3). Gastric adenocar-
cinoma, especially of the intestinal type, is believed to arise
via a multistage process that includes chronic gastritis, gas-
tric atrophy, intestinal metaplasia, and finally dysplasia (4).
Intestinal metaplasia is classified into complete (I) and in-
complete (II & III) types depending on the secreted mucin
and mucosal characteristics, and these subtypes may exist con-
comitantly in a patient (5, 6). Intestinal metaplasia has long
been considered to play an important role in the development
of gastric carcinoma. Type III incomplete intestinal metapla-
sia was found to be more common in the mucosa of gastric
carcinoma than in the mucosa of chronic gastritis and greater
number of genetic mutations developed in incomplete meta-
plasia (6-9). The rate of evolution into gastric carcinoma was
4.58 times higher in type III intestinal metaplasia than in
type I intestinal metaplasia (10). These findings suggest that
incomplete intestinal metaplasia carry a higher risk for devel-
opment of gastric carcinoma than complete intestinal meta-
plasia. However, several studies did not show the relation
between type III intestinal metaplasia and gastric carcinoma
(11, 12). Therefore, further studies are necessary to determine
the role of the subtypes of intestinal metaplasia as a marker
for gastric carcinoma.
The mutation of the p53 gene is one of the most represen-
tative genetic abnormalities in gastric carcinoma. p53 muta-
tioncould also be observed in intestinal metaplasia with 2.5-
50% incidence reported (13-15). The mutation was more
commonly observed in incomplete intestinal metaplasia than
in complete intestinal metaplasia.
Microsatellite instability (MSI) is a mutator phenotype that
occurs through a loss of the mismatch repair system in cells,
and contribute to the generation of cancer by inducing muta-
tions of oncogenes and tumor suppressor genes (16, 17). In
gastric carcinoma, MSI is noted in the early stages of cancer
development and is shown in 13-44% of cases (18-20). The
frequency of MSI in intestinal metaplasia was variable, rang-
ingfrom 0% to 48% (18, 21-24).
However, these reports made their comparison on different
specimens from different patients. There have been few reports
that studied these genetic abnormalities according to the sub-
typesof intestinal metaplasia in a single patient.
The present study was aimed to investigate the potential
implication of the subtype of intestinal metaplasia in the rela-
tionship between intestinal metaplasia and gastric carcinoma
by comparing the mutations of the p53 gene and MSI in the
complete type (type I) intestinal metaplasia and those in the
Sung Soo Kim, Choon Sang Bhang,
Ki Ouk Min*, Hiun Suk Chae,
Sang Wook Choi, Chang Don Lee,
Keun Woo Lim
�, In Sik Chung, Doo Ho Park
Division of Gastroenterology, Department of Internal
Medicine, Department of Clinical Pathology*, and
Department of Surgery
Catholic University of Korea, Seoul, Korea
�, College of Medicine,
Address for correspondence
Doo Ho Park, M.D.
Division of Gastroenterology, Department of Internal
Medicine, Kangnam St. Mary's Hospital, 505
Banpo-dong, Seocho-gu, Seoul 137-040, Korea
Tel : +82.2-590-1341, Fax : +82.2-590-2387
E-mail : email@example.com
*This research was supported by grants from the
Korea Research Foundation (KRF-2000-003-F00099).
J Korean Med Sci 2002; 17: 490-6
Copyright � The Korean Academy
of Medical Sciences
p53 Mutations and Microsatellite Instabilities in the Subtype of
Intestinal Metaplasia of the Stomach
To investigate the potential implication of the subtype of intestinal metaplasia in
the progression to the gastric carcinoma, we analyzed the mutations of the p53
gene and microsatellite instability (MSI) both in the complete type (type I) and in
the sulphomucin-secreting incomplete type (type III) intestinal metaplasia locat-
ed adjacent to the gastric carcinoma. p53 mutations were observed in 13.3% of
type I, in 6.6% of type III intestinal metaplasia, and in 40% of gastric carcinoma.
The difference between p53 mutations observed in type I and type III intestinal
metaplasia was not statistically significant. No identical mutation of the p53 gene
was found in the intestinal metaplasia and carcinoma specimens from the patients.
There was no case of intestinal metaplasia showing MSI. In gastric carcinomas,
MSI was observed in six cases (40%). The cases harboring BAT-26 instability
did not have the mutation of the p53 gene. These data suggest that intestinal meta-
plasia adjacent to gastric carcinoma, irrespective of its subtype, do not have the
genetic alterations as showing in their carcinoma tissues.
Key Words : Intestines; Metaplasia; Subtype, Genes p53; Mutation; Microsatellite Repeats
Received : 6 February 2002
Accepted : 29 April 2002
sulphomucin-secreting incomplete type (type III) intestinal
metaplasia located adjacent to the gastric carcinoma.
MATERIALS AND METHODS
The study subjects were 15 patients with intestinal type
gastric carcinoma operated at St. Mary's Hospital of Catholic
University of Korea. The tissue specimens of both complete
(type I) and incomplete (type III) intestinal metaplasia were
acquiredfrom resected normal tissues adjacent to the gastric
carcinoma. The neutral mucin and acidic sialomucin in intesti-
nal metaplasia was confirmed by alcian blue (pH 2.5)/ peri-
odic acid Schiff stain and the sulphomucin was confirmed by
highiron diamine/alcian blue (pH 2.5) stain. Type I intestinal
metaplasia was determined by the presence of goblet cells
that secrete acidic sialomucin (stained blue) between nonsecret-
ing absorptive cells as well as the presence of brush border
and in some cases, Paneth cells at the crypt base. Type III
intestinal metaplasia was determined by presence of abun-
dant immature columnar cells and also secretion of sulpho-
mucin (stained brown) by cells (5). The type III intestinal
metaplasia, although it was scarse in non-cancerous stomach,
was detected frequently in the mucosa adjacent to gastric car-
cinoma. We selected the specimens contained much of type
III intestinal metaplasia enough to extract DNA. The forma-
lin-fixed, paraffin-embedded specimens of type I, type III
intestinal metaplasia, and carcinoma were sectioned twice
Intestinal Metaplasia as Precancerous Lesion
Fig. 1. Microdissection. (A) an area of gastric epithelial gland be-
fore microdissection showing intestinal metaplasia surrounded
by stromal cells (H&E, original magnification,×100). (B) the gland
easily peels off from the slide during the microdissection. (C) the
gland was dissected out, leaving a large hole behind.
with 7- m thickness for DNA extraction. The lymph node
was used as negative control.
After deparaffinization, the tissue specimens were H&E
stained and placed in glycerol buffer [2% glycerol in TE buffer
(10 mM Tris, pH 8.0, 1 mM EDTA)] for 2 min. After wip-
ing the back of the slide, the specimens were observed under
a light microscope with 40-100-fold magnification. Tissues
were extracted with 31-gauge (Becton Dickinson, Franklin
Lake, NJ, U.S.A.) needles (Fig. 1), and were placed in a 30- L
lytic solution (0.5% Tween 20, 1 mM EDTA, pH 8.0, 50 mM
Tris-HCl pH 8.5). The process was repeated until 1,500-2,000
cells were collected. After proteinase K (2 mg/mLof lytic solu-
tion; Promega, WI, U.S.A.) was added, the mixturewas incu-
batedfor 48 hr at 37℃.
Sequencing analyses of the p53 gene
Exon 5 to 8 of the p53 gene were amplified by the poly-
merase chain reaction (PCR). The PCR premix included 2.5
L of the template DNA, 5 L of 5 pmol/ L primer (25), 3
L of 1.25 mM MgCl2, 5 L of 1.25 mM dNTP, 0.5 L of
5 units/ L of Taq DNA polymerase (TaKaRa Biomedicals,
Shiga, Japan), 5 L of 10×buffer, and distilled water to a
final volume of 50 L. PCR reaction was performed immedi-
atelyusing the MJR thermal cycler (MJ Research Inc., Water-
town, MA, U.S.A.); 1 cycle at 99℃ for 5 min for denatura-
tion of the template DNA and 32 cycles at 94℃ for 50 sec,
62℃ for exons 5, 7, 8 and 66℃ for exon 6 for 50 sec, and
72℃for 1 min. The amplified DNA were confirmed by elec-
trophoresison 2% agarose gel (Sigma Chemical Co., St. Louis,
MO,U.S.A.) (Fig. 2).
The DNA sequencing was performed on both DNA strands
using the enzymatic dideoxy chain termination sequencing
chemistry with the four different nucleotides labeled with
different fluorescent dyes (BigDye terminator cycle sequenc-
ing kit; Perkin Elmer, U.S.A.). Automated gel reader (Auto
DNA Sequenser 377XL, Applied Biosystem, U.S.A.) using
argon laser beam read the sequence trace. The sequence traces
were transferred to a computer file where they can be manu-
ally edited and further analyzed with dedicated software. The
terminator premix included the thermally stable enzyme,
Ampli TaqDNA polymerase FS, dITP, 8 L of BigDye pre-
mix, 300 ng of template DNA, 5 pmoles of primer, and dis-
tilled water to a final volume of 20 L. It was mixed well by
vortexing. PCR reaction was performed immediately using
the Perkin Elmer GenAmp 9700 thermal cycler (U.S.A.); 1
cycle at 95℃for 1 min for denaturation of the template DNA
and 30 cycles at 96℃for 15 sec, 55℃for 15 sec, and 60℃
for 4 min. After PCR amplification, excess BigDye termina-
tors were removed from the sequencing reaction by using
spin columns or ethanol washing. The purified samples were
placed onto a sequencing gel on one lane.
Analyses of microsatellite instability
Mononucleotide markers BAT-25 and BAT-26, and dinu-
cleotide markers D2S123, D5S346, D13S170, D17S250,
and TP53 were used in the analyses of MSI (26-30). PCR
premix included 1 L of the template DNA, 0.4 M of primer,
125 M of dNTP, 1.5 mM of MgCl2, 0.4 unit of Taq DNA
polymerase, 0.5 mCi of [32P]dCTP (Amersham, Bucking-
hamshire, United Kingdom) and 1 L of 10×buffer mixed
to a total reaction volume of 10 L. The mixture was ampli-
fied using the MJR thermal cycler (MJ Research Inc.); 1 cycle
at 95℃for 5 min for denaturation of the template DNA, 35
cycles at 95℃ for 1 min, annealing at defined temperatures
on the references for 1 min, and 72℃ for 1 min, and 1 cycle
at 75℃ for 5 min. Two microliters of the PCR product was
mixed with 10 L of loading dye (95% formamide, 20 mM
EDTA, 0.05% xylene cyanol FF, and 0.05% bromophenol
blue) and denatured at 95℃for 5 min. The sample was load-
ed in a denaturing gel (8.3 M urea and 8% acrylamide) and
electrophoresed for 3 hr. After electrophoresis, the gel was
fixed and dried onto 3 mm Whatmann paper and DNA ab-
normality was analyzed through autoradiography using Ko-
dak-OMAT film (Eastman Kodak, Rochester, NY). DNA
bands that were different in size from those obtained from
normal lymph node were considered to harbor MSI. BAT-
26 instability was regarded as the representative marker of
high frequency MSI.
Mutation of the p53 gene
Of the 15 cases, mutation in the p53 gene was found in 2
cases of type I intestinal metaplasia (13.3%), one case of type
III intestinal metaplasia (6.6%), and in 6 cases of gastric car-
cinoma (40%). There was no identical mutation between in-
testinal metaplasia and carcinoma. All the detected mutation
of the p53 gene was missense mutation in which an amino
acid is replaced by another amino acid. Case No. 11 had a
silent mutation in which the altered codon coded for the same
protein (CTG→TTG, Leucine). The case No. 5 had a muta-
S.S. Kim, C.S. Bhang, K.O. Min, et al.
Fig. 2. Agarose gel electrophoresis of amplified products of the
p53 gene, exon 5 to 8, in the DNA from normal (N), type I (I) and
III (III) intestinal metaplasia, and gastric carcinoma (T).
N III T
IN III T
IN III T
tion in the splice junction between intron 7 and exon 8 (AG
→AT) in the type III intestinal metaplasia. Of the nine p53
gene mutations, four were observed in exon 5, two in exon
6, two in exon 7, and one in exon 8 (Table 1 and Fig. 3).
In the intestinal metaplasia, no case showed microsatellite
instability. Microsatellite instabilities were observed in 6 cases
(40%) of gastric carcinoma. Among these, case No. 5, 9, and
10 showed high frequency MSI, including BAT-26 instabil-
ity. In case No. 1 and 7, the instability was detected in single
dinucleotide marker as in D17S250 and D13S170, respec-
tively. Case No. 4 showed instabilities in two dinucleotide
markers, D17S250 and TP53. Loss of heterozygosity was ob-
served in 4 cases of gastric carcinoma (26%) (Table 2 and
Intestinal Metaplasia as Precancerous Lesion
MSI-L (D17S250, TP53)
MSI-H (BAT-25, BAT-26, D13S170,
MSI-H (BAT-25, BAT-26, TP53)
MSI-H (BAT-25, BAT-26, D5S346,
LOH (D13S170, D17S250, TP53)
Case No. IM type IIM type III Carcinoma
Table 2. Microsatellite instabilities and loss of heterozygosity
in the intestinal metaplasia and gastric carcinoma
IM, intestinal metaplasia; LOH, loss of heterozygosity; MSI-L, low fre-
quency microsatellite instability; MSI-H, high frequency microsatellite
Fig. 4. Microsatellite instability analysis. For each of the 7 mono-
and dinucleotide markers, autoradiograms of microsatellite insta-
bility and loss of heterozygosity for three selected cases are shown.
Each autoradiogram has four lanes indicating normal, type I and
type III intestinal metaplasia, and carcinoma, respectively. Case
No. 5 exhibits microsatellite instability in 5 loci (BAT-25, BAT-26,
D13S170, D17S250, and TP53), case No. 10 reveals microsatel-
lite instability in 5 loci (BAT-25, BAT-26, D5S346, D13S170, and
TP53), and case No. 15 shows loss of heterozygosity in three loci
(D13S170, D17S250, and TP53).
BAT-25 BAT-26 D2S123 D5S346 D13S170 D17S250TP53
Fig. 3. Sequencing histograms of p53 mutation. Arrows, site of
mutation; WT, wild type sequence; MT, mutant sequence; *, re-
E6, L194F (CTT→TTT)
E7, G245D (GGC→GAC)
: splicing mutation
E6, H193R (CAT→CGT)
11 E5, L145L (CTG→TTG)
: silent mutation
E5, Q136E (CAA→GAA)
E5, R175H (CGC→CAC)
E5, C176F (TGC→TTC)
Case No.IM type I IM type IIICarcinoma
Table 1. p53 mutations in the intestinal metaplasia type I and III,
and gastric carcinoma
IM, intestinal metaplasia; E, exon; In, intron.
*, codon number.
glutamic acid; F, phenylalanine; G, glycine; H, histidine; L, leucine; N,
asparagine; Q, glutamine; R, arginine; V, valine).
�, amino acid codes (C, cysteine; D, aspartic acid; E,
The relationship between microsatellite instabilities and
The case harboring MSI tended not to have mutation of the
p53 gene. Of the total six cases with MSI, only one case (case
No. 4) with low frequency MSI had a mutation of the p53
gene in the gastric carcinoma. Cases with the BAT-26 insta-
bilityhad no concomitant mutation of the p53gene (Table 3).
Mutation of the p53gene and microsatellite instability have
been previously studied in subtypes of intestinal metaplasia
by immunohistochemical and molecular genetic techniques,
and much of genetic abnormalities were observed in the in-
complete type intestinal metaplasia (9, 13-15). However,
these reports compared the intestinal metaplasia from dif-
ferent specimens of different patients. In this study, DNA of
type I and type III intestinal metaplasia was extracted from
the same patient, and p53 mutation and MSI were analyzed.
The results revealed no genetic differences between type I
and type III intestinal metaplasia adjacent to their carcinoma
The incidence of p53mutation in intestinal metaplasia was
reported as 2.5-50% (13-15). Shiao et al. reported that p53
mutations occurred in four out of eight (50%) intestinal meta-
plasia by the polymerase chain reaction-single stranded con-
formational polymorphism (PCR-SSCP) and nucleotide se-
quence analysis (13). Gomyo et al. reported two cases with
p53 mutations from 21 cases with intestinal metaplasia
(9.5%), and they were all incomplete type intestinal meta-
plasia (14). Ochiai et al. have demonstrated that 2.5% of posi-
tive immunohistochemical stain for p53 was incomplete type
intestinal metaplasia (15).
Cancers often harbor the same genetic abnormalities with
the premalignant lesions, which provide evidence of mono-
clonal expansion of mutated cells. This finding can be ob-
served in various cancers, such as actinic keratosis and skin
melanoma as well as dysplasia and gastric carcinoma (13, 31).
In limited studies on intestinal metaplasia, the same p53mu-
tation was found both in intestinal metaplasia and gastric
carcinoma. However, this was not always the case. In some
cases, p53 mutation in intestinal metaplasia was different
from that in carcinoma. In this study, there was no identical
mutation of the p53 gene between intestinal metaplasia and
carcinoma. Shiao et al. showed that out of 4 cases of intesti-
nal metaplasia with p53 mutation, one case did not have the
same mutation in the gastric carcinoma (13). Gomyo et al.
reported that one of two cases did not have same mutation of
the p53 gene in intestinal metaplasia and in carcinoma (15).
As suggested by Shiao et al., these findings can be explained
by genetic alteration of a small population of cells due to in-
stability of the p53gene, which may not be detected by DNA
sequencing (13). The other possibility may be that not all
the p53 mutations exhibited on intestinal metaplasia portend
a progression to carcinoma. Some cases of intestinal metapla-
sia may be fatal before they proceed to cancer, or may be at
an ongoing step for development of carcinoma.
In this study, MSI was observed in 40% (6/15) of cases with
gastric carcinoma, and these result was comparable to those
reported in literature (18-20). However, intestinal metapla-
sia showed no MSI. In the literature, MSI in the intestinal
metaplasia has been frequently observed, ranging from 27%
to 48% (18, 21-23). MSI reported in intestinal metaplasia was
present at a few dinucleotide microsatellite markers. There
was no BAT-26 instability, which was known as the marker
of mismatch repair defects, in intestinal metaplasia. MSI at
a few dinucleotide microsatellite markers may not necessari-
ly be the result of defective mismatch repair, if it is not asso-
ciated with BAT-26 instability (24). In a recent study using
BAT-25, BAT-26, D2S123, D5S346and D17S250, there was
no instability of these markers in intestinal metaplasia adja-
cent to gastric carcinoma (24). This study was similar with
our study in the tissue specimens used, MSI markers, and the
results. The discrepancies in MSI frequencies in the reports
may result from differences in sample selection, data inter-
pretation and/or microsatellite markers used.
In this study, among the six cases of gastric carcinoma with
MSI, only one case had an accompanying mutation of the p53
gene. Cases having BAT-26 instability, which is regarded as
a representative marker for MSI, had no concomitant muta-
tion of the p53 gene. This finding is in line with those from
other studies. MSI often accompanies other genetic abnormali-
ties, mainly of the -catenin and transforming growth factor
receptor type II genes. On the other hand, mutations of the ade-
nomatous polyposis coli (APC) gene and the p53 genes appeared
to be rarely accompanied by MSI (32-35). A recent study
S.S. Kim, C.S. Bhang, K.O. Min, et al.
Case No. p53 mutationMicrosatellite instability
Table 3. The relation between microsatellite instabilities and p53
mutations in gastric carcinoma
MSI-L, low frequency microsatellite instability; MSI-H, high frequency
showed that there was no correlation between MSI andmuta-
tion of the p53 gene, suggesting that p53 mutation might
not be generated by MSI (35).
The present study suggests that intestinal metaplasia adja-
cent to gastric carcinoma, irrespective of its subtype, do not
have the genetic alterations as showing in their carcinoma
tissues. Further studies may be needed with the other genetic
markers, and with the larger amount of samples for the pur-
pose of discrimination of potential role of intestinal metapla-
siaas a precancerous lesion.
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