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Yu-Ping Xiao,
Cheng-Bo Han, Xiao-Yun Mao, Jin-Yi Li, Lei Xu, Chang-Shan Ren, Yan
Xin, Cancer Institute, the First Hospital of China Medical
University, Shenyang 110001, Liaoning Province, China
Supported by the National Natural Science Foundation of
China, No. 30371607
Correspondence to: Professor Yan Xin, the Fourth Laboratory
of Cancer Institute, the First Hospital, China Medical University,
Shenyang 110001, Liaoning Province, China.
yxin@mail.cmu.edu.cn
Telephone: +86-24-23256666-6351
Received: 2004-06-07
Accepted: 2004-06-24
Abstract
Aim: To examine
the aberrant expression of fragile histidine triad (FHIT) gene and
protein in gastric cancer, and to evaluate the role of FHIT gene and
the relationship between FHIT gene and EBV infection in gastric
carcinogenesis.
Methods: FHIT
transcripts were detected by nested RT-PCR in 30 cases of gastric
cancer and their products were sequenced. FHIT protein was detected
by Western blot. EBV infection was detected by PCR method in 50
cases of gastric cancer.
Results: The
wild type transcripts were detected in all 30 matched normal tissues
of gastric cancer. Aberrant transcripts were found in 11/30 (36.7%)
gastric cancerous tissues. Sequencing analysis of the aberrant
fragments found an RT-PCR product missing exons 5-7 in one case of
gastric cancer, and another product missing exons 4-7. Four of ten
(40.0%) cases of primary gastric cancer showed absent or decreased
expression of FHIT protein as compared with their matched normal
tissues. EBV was detected in 5/50 (10%) gastric cancers, among which
4/5 (80%) had aberrant transcripts of FHIT gene.
Conclusion:
Loss of FHIT gene or FHIT protein p1ays an important role in
carcinogenesis, development and progression of gastric cancer. EBV
infection might influence carcinogenesis of gastric cancer by
inducing the abnormality of FHIT gene.
ã 2005
The WJG Press and Elsevier Inc. All rights reserved.
Key words: Gastric carcinoma; Fragile histidine triad;
Epstein-Barr virus; LOH
Xiao YP, Han CB, Mao XY, Li JY, Xu L, Ren CS, Xin Y. Relationship
between abnormality of FHIT gene and EBV infection in gastric
cancer. World J Gastroenterol
2005; 11(21): 3212-3216
http://www.wjgnet.com/1007-9327/11/3212.asp
INTRODUCTION
Gastric carcinogenesis has been thought to be associated with
its highly exposed risk factors such as Helicobacter pylori
infection[1]
and excessive nitrite salt intake[2-4].
In recent years, close attention has been paid to the carcinogenic
factor of Epstein-Barr virus (EBV)[5-8].
It has been known that multiple oncogenes and tumor suppressor genes
are involved in gastric carcinogenesis, however, no specific
oncogenes and tumor suppressor genes have been identified. Fragile
histidine triad (FHIT) gene, a tumor suppressor gene, is located at
chromosome 3p14.2 and contains the most common aphidicolin-induced
fragile site FRA3B[9].
FRA3B is the non-randomly fragmental or fissured site through
chromosome's spontaneous
or induced actions, and also susceptible to chromosome loss and
rearra-ngement because of the frequent fragmentation or fissure,
which might be related to tumorigenesis[9].
Moreover, one of the EBV pathogenesis mechanisms might be related to
the integration of EBV DNA into FRA3B and consequently decreasing
FRA3B compliance[10].
Considering that FHIT contains the FRA3B region, EBV might make FHIT
inactivated leading to carcinogenesis. In this paper, mRNA and
protein expression of FHIT gene, EBV infection and their
relationship in gastric carcinogenesis was determined.
MATERIALS AND METHODS
Materials
Specimens, including 50 cases of primary gastric cancerous
and matched distant normal gastric mucosal tissues, were surgically
resected at the First Hospital of China Medical University without
preoperative chemotherapy and radiotherapy. They were put
immediately into liquid nitrogen, and reserved at -70 ℃.
All cases were classified respectively by Borrmann, WHO histological
classification, Lauren classification, invasive depth and lymph node
metastasis.
Methods
DNA and RNA extraction DNA was extracted from frozen gastric
cancerous and normal mucosal tissues by standard phenol-chloroform
method[6,8],
dissolved and reserved in TE buffer[11].
RNA extraction was conducted according to instruction of TRIzol
reagent kit (GIBCO). Briefly: frozen gastric tissues were ground
into pieces, homogenized in l mL TRIzol reagent using a homogenizer
for 30 s, and incubated for 5 min. and then 200 mL
chloroform was added and spun by centrifugation at 3 000 r/min for
15 min. The aqueous phase was transferred to another Eppendorf tube,
500 mL
isoamyl alcohol was added and placed on ice for 1 h, and spun by
centrifugation at 3 000 r/min for 15 min, finally, the supernatant
was discanded, RNA pellet was washed once with 750 mL/L ethanol,
dissolved in 1 mL/L DEPC sterile water, and kept at -20 ℃.
PCR and nested RT-PCR PCR and nested RT-PCR were used to
amplify the EBV DNA and FHIT mRNA, respect-ively. Primer sequence
for EBV was: (F)5'-CCAGACAGCA-GCCAATTGTC-3';
(R)5'-GGTAGAAGACCCCCTC-TTAC-3'. The PCR product was 129 bp in
length, spanning the BamH1-w of EBV. PCR amplification was carried
out in a final volume of 25 mL,
containing 50 ng DNA, 0.5 mmol/L
of each primer, 200 mmol/L
of each dNTP, and 0.5 U Taq DNA polymerase (TaKaRa Ex TaqTM).
The amplification condition: an initial incubation at 94 ℃
for 3 min, followed by 30 cycles of 94 ℃
for 30 s, 58 ℃
for 30 s and 72 ℃
for 1 min; and the final step of extension at 72 ℃
for 5 min. The cDNA synthesis of RT-PCR referred to the instruction
of BcaBEST RNA PCR kit (TaKaRa). Nest-PCR primers were: (F2)5'-ATCCTGGAAGCTTTGAAGCTGA-3';
(R2)5'-TCACTGGTTGAAGAATACAGG-3'; (F1)5'-TCCGTA-*CTGCTATCTACATC-3';
(Rl)5'-CATGCTGATTCA-GTTCCTCTTGC-3'.First cycle of nest-PCR was the
same as aforementioned except for PCR reaction volume 25 mL
containing 50 ng cDNA, 0.5 mmol/L of each outer primer F2 and R2.
The second cycle reaction system contained 5 mL of the first cycle
product and 0.5 mmol/L of each inner primer F1 and R1, the others
were similar.
Polyacrylamide gel electrophoresis (PAGE) EBV PCR products
and nest-PCR products of FHIT gene in gastric cancerous and matched
normal tissues were run on 1.5% agarose gel in 1 TBE buffer at a
constant voltage of 60 V for 1 h.
Sequencing Abnormal nest-PCR products confirmed with agarose
gel electrophoresis were cloned and sequenced by AoKe Biology
Company (Beijing, China).
Protein extraction Tissues were sheared and homogenized in a
homogenizer, added with suspending buffer containing 2 mmol/L EDTA,
10 mmol/L EGTA, 20 mmol/L
Tris-HCl, pH 7.5, 56 g/L sucrose and 100 g/L PMSF, agitated with
ultrasonic instrument, then spun by centrifugation at 4 ℃
13 000 g for 1 h. The supernatants were collected for Western
blot.
Western blot Sixteen microliters of protein extracts were
added into 4 mL
5×sampling buffer containing 130 mmol/L
Tris-Cl, pH 8.0, 200 mL/L glycerol, 46 g/L SDS, 20 g/L DTT,
pre-denatured at 96 ℃
for 10 min, run on 12% polyacrylamide gel (PAGE), then transferred
to pyroxylin membrane at a voltage of 300 V for 2 h. The membrane
was soaked in 1×TBS
for approximately 10 min, and rabbit anti-human FHIT antibody
(SANsc-8215, Gene Company Ltd) added at room temperature overnight,
rinsed with 1×TBS buffer, goat anti-rabbit IgG
antibody (Zhongshan Company, Beijing, China) added, shaken gently
for 1 h, and rinsed with 1×TBS again. Finally Horseradish
peroxidase (HRP) was added for 30 min and color development was done
with DAB for 15-30 min, and membrane was rinsed with distilled water
to stop reaction.
Statistic analysis
c2-test
was applied with SPSS software (version 10.0 for Windows). A P
value of less than 0.05 was considered statistically significant.
RESULTS
Abnormal transcripts of FHIT gene in gastric cancer
The normal transcripts (wild type, 707 bp) of FHIT gene were
detected out in 30 cases of matched normal gastric mucosa. Abnormal
transcripts were found in 11 of 30 cases (36.7%) of gastric cancers,
among which five were shorter than 500 bp in length. Three cases of
gastric cancers were simultaneously accompanied with normal
transcripts, one with complete loss. Repeated experiments suggested
that there existed FHIT gene loss in gastric cancer (Figure 1).
Figure 1 (PDF)
Deletion of FHIT gene in gastric cancer. Lanes T3 and T4 show
truncated FHIT gene.
Sequencing results
After two abnormal transcripts were purified via gel
electrop-horesis, the following sequencing results showed that one
lost exons 5-7 of FHIT gene with a deletion of 297 bp and connection
of exon 4 and exon 8; the other lost exons 4-7, with a deletion of
389 bp and connection of exon 3 and 8. In addition, all losses
occurred in exon joints (Figures 2 and 3).
Figure
2
(PDF) Sequencing
analysis of abnormal FHIT gene expression. Arrow indicates the
splicing joint of FHIT gene exons 4 and 8.
Figure
3
(PDF) Sequencing analysis of abnormal FHIT gene expression.
Arrow indicates the splicing joint of FHIT gene exons 3 and 8.
FHIT protein expression and EBV infection in gastric cancer
Western blot showed 4 of 10 cases (40.0%) of gastric cancers had
loss or decreased expression of FHIT protein (Figure 4). EBV was
detected in 5 of 50 (10%) cases of gastric cancers (Figure 5), among
which 4 out of 5 (80.0%) has abnormal FHIT gene transcripts. The
relationship between EBV infection and FHIT gene expression in
gastric cancer is shown in Table 1.
Figure
4
(PDF) Expression of
FHIT protein in gastric cancer. Lane T1 shows the deletion of FHIT
protein. N: normal; T: tumor.
Figure
5
(PDF) Electrophoresis result of EBV in gastric cancer. Lanes
2, 6-8 show the positive EBV infection.
Table 1 Relationship
between EBV infection and FHIT transcripts
| |
|
FHIT
Transcripts |
| EBV |
n |
Abnormal |
Normal |
| + |
5 |
4 |
1 |
| - |
45 |
7 |
38 |
| Sum |
50 |
11 |
39 |
P
= 0.006, EBV+ vs EBV-.
DISCUSSION
Exon 5 of FHIT gene is the first coding exon (initiation of
translation), adjacent to fragile site FRA3B. DNA repair and
rearrangement of FRA3B fissured site result in deletion of FHIT gene
exon. Exon 8 containing highly conserved region, is a
combing site of zinc ion and also the important target region
of FHIT gene loss. The coding protein of FHIT gene, FHIT, a typical
dinucleotide triphosphoric acid hydrolase (Ap3A), could hydrolyze
adenosine diphosphate into ADP and AMP[12].
FHIT combines with mRNA cap structure, making mRNA de-cap, loss of
function, increasing the probability of tumorigenesis[12].
FHIT combines with its substrate and exerts tumor suppression by its
compound, which might be a signaling molecule and has more important
function than its hydrolase[13].
Our research showed that FHIT gene in 36.7%
gastric cancers presented truncated or deleted transcripts, about
450, 350, and 280 bp in length, suggesting there were different
deletions of FHIT gene in gastric cancer. Sequencing results showed
FHIT gene had deletion of exons 5-7 and
4-7. The deleted sites of FHIT transcripts were all splicing
sites of FHIT gene exons, suggesting that deletion of FHIT gene
usually resulted from its abnormal splice.
Baffa et al.[14],
reported that 53% gastric cancers had abnormal transcripts of FHIT
gene, and 67% showed loss expression of FHIT protein. Huiping et
al.[15]
, also reported that 87% gastric caners
presented abnormal transcripts of FHIT gene. Ohta et al.[16],
discovered via nest RT-PCR that 53.6% gastric cancers and 37.5%
large intestinal cancers had abnormal transcripts of FHIT gene,
suggesting deletion of FHIT gene was common in gastric cancer.
Abnormal transcripts of FHIT gene often involved one or more exons
deletion, and mostly occurred in the two important functional exons
5 and 8, which were defined as types I and II, respectively by Ohta
et al [16].
Whether types I or II, abnormal transcripts could not encode fully
functional FHIT protein, so the two exons deletion might play a very
important role in carcinomatous change of gastric mucosal
epithelium. We summarize the abnormalities of FHIT gene transcripts
as follows: (1) Exons 4-6 deletion; (2) exons 4-8 deletion; (3)
single one exon deletion such as exon 5 or exon 8; (4) whole
transcript's
deletion. The deletion of FHIT
transcripts often involved important functional exons 5 and 8,
further influencing the function of FHIT protein, resulting in a
decrease or loss of FHIT protein activity, which affected catabolism
of Ap3A and Ap4A. Accumulated intracellular Ap3A and
Ap4A could repress cell apoptosis, and induce cell carcinomatous
change[17-20].
Previous reports[21-22]
showed that frequent deletions of FHIT transcripts were accompanied
with decrease or loss of FHIT protein. Our researches showed that
40% gastric cancers displayed decreased or depleted FHIT protein
(statistic analysis was not performed for fewer cases), and all of
them had lymph node metastasis, suggesting that a decreased FHIT
protein might be associated with lymph node metastasis and poor
prognosis. Otterson et al [23],
found that over-expression of FHIT protein could not suppress the
cell clonal formation and cell proliferation. When transfer of
normal FHIT gene into cancer cells without wide type FHIT per se,
the product FHIT protein, however, could not suppress the cell
growth. We presumed that the molecular mechanism of FHIT gene
might be intrinsically different from the traditional tumor
suppressor gene such as p53.
It has been found[5-7,24,25]
that some gastric carcinomas are associated with the infection of
EBV since Shibata et al.[26],
firstly reported their relationship. Most of the gastric
carcinomas associated with EBV (EBVaGC) occurred at cardia or body
of the stomach, or just appeared in the remnant gastric cancer, and
showed the malignant features such as poor differentiation and
infiltrated lymph nodes. We found five cases of gastric cancers
infected with EBV and simultaneously all of them had lymph node
metastasis, among which three cases were poorly differentiated
late-stage gastric cancers, one moderately differentiated
early-stage, and one poorly differentiated middle-stage gastric
cancer. From the view of clinicopathological features, EBVaGC tended
to be poorly differentiated, with lymph node metastasis, suggesting
a poor prognosis of gastric cancer.
Divergent opinions have been reported concerning
the molecular mechanism of EBVaGC. Some researchers[27-29]
proposed that EBVaGC was associated with the abnormality of P53,
Bcl-2, and TGF-b,
and microsatellite instability. Chang et al.[30],
thought that there was no correlation between the infection of EBV
and gastric carcinomas. At present, the mechanism of EBV in
promoting gastric carcinogenesis has been unknown. Ohta et al.[16],
discovered that abnormalities of FHIT were frequently observed in
some malignant tumors in certain areas, such as nasopharyngeal
carcinomas in China and gastric cancers in Southeast Asia, and EBV
might result in abnormal FHIT gene by its integration into the
region of FRA3B. Four of the five gastric cancers with EBV infection
in our study presented abnormal transcripts, indicating the close
association between EBV and the abnormality of FHIT gene, and even
the cell carcinomatous change. We also detected the loss of
heterozygosity (LOH) and microsatellite instability (MSI) in the
same five cases. LOH was observed at microsatellite sites D3S4103
(4/5), D3S1300 (3/5), D3S1481 (2/5) and D3S1234 (2/5), while MSI
appeared at sites D3S1300 (1/5), D3S1481 (1/5) and D3S1234 (1/5). As
D3S4103, D3S1300 and D3S1481 all located near exon 5 of FHIT gene,
we presume that the integrating site of EBV might be just near exon
5.
In conclusion, we supply some new clues for
further studies on the relations between abnormal FHIT and the
malignant biological behaviors of gastric cancer cells. The studies
of the relationship between EBV infection and abnormality of FHIT
gene also provide a new scientific basis on pathogenesis of gastric
cancer. By a certain mechanism such as integration, EBV might result
in FHIT gene instability, down-regulate transcripts or truncated
(deleted) FHIT proteins, which are likely to play an important role
in gastric carcinogenesis, local infiltration and regional lymph
node metastasis.
REFERENCES
1
Nardone G, Rocco A, Vaira D, Staibano S, Budillon A,
Tatangelo F, Sciulli MG, Perna F, Salvatore G, Di Benedetto M,
De Rosa G, Patrignani P. Expression
of COX-2, mPGE-synthase1, MDR-1 (P-gp), and Bcl-xL: a molecular
pathway of
H pylori-related gastric
carcinogenesis. J Pathol 2004; 202: 305-312
2
Mayne ST, Risch HA, Dubrow R, Chow WH, Gammon MD,
Vaughan TL, Farrow DC, Schoenberg JB, Stanford JL, Ahsan
H, West AB, Rotterdam H, Blot WJ,
Fraumeni JF Jr. Nutrient intake and risk of subtypes of esophageal and
gastric
cancer. Cancer Epidemiol
Biomarkers Prev 2001; 10: 1055-1062
3
Palli D. Epidemiology of gastric cancer: an evaluation
of available evidence. J Gastroenterol 2000; 35:
84-89
4
Van Loon AJ, Botterweck AA, Goldbohm RA, Brants HA,
van Klaveren JD, van den Brandt PA. Intake of nitrate and
nitrite and the risk of gastric
cancer: a prospective cohort study. Br J Cancer 1998; 78:
129-135
5
Sudo M, Chong JM, Sakuma K, Ushiku T, Uozaki H, Nagai
H, Funata N, Matsumoto Y, Fukayama M.
Promoter hyperme-thylation of E-cadherin
and its abnormal expression in Epstein-Barr virus-associated
gastric
carcinoma. Int J Cancer 2004; 109:
194-199
6
Van Beek J, zur Hausen A, Klein Kranenbarg E, van de
Velde CJ, Middeldorp JM, van den Brule AJ, Meijer CJ,
Bloemena E. EBV-positive gastric
adenocarcinomas: a distinct clinicopathologic entity with a low
frequency of lymph
node involvement. J Clin Oncol 2004;
22: 664-670
7
Oh ST, Seo JS, Moon UY, Kang KH, Shin DJ, Yoon SK, Kim
WH, Park JG, Lee SK. A
naturally derived gastric cancer
cell line shows latency I
Epstein-Barr virus infection closely resembling EBV-associated
gastric cancer. Virology
2004; 320: 330-336
8
Lee HS, Chang MS, Yang HK, Lee BL, Kim WH. Epstein-barr
virus-positive gastric carcinoma has a distinct
protein expression profile in
comparison with epstein-barr virus-negative carcinoma. Clin
Cancer Res 2004;
10: 1698-1705
9
Mimori K, Inoue H, Shiraishi T, Matsuyama A, Mafune K,
Tanaka Y, Mori M. Microsatellite instability is often observed
in esophageal carcinoma patients with
allelic loss in the FHIT/FRA3B locus. Oncology 2003; 64:
275-279
10
Lee HS, Chang MS, Yang HK, Lee BL, Kim WH. Epstein-barr
virus-positive gastric carcinoma has a distinct
protein expression profile in
comparison with Epstein-barr virus-negative carcinoma. Clin
Cancer Res 2004;
10: 1698-1705
11
Han CB, Zhao YJ, Li F, He Q, Ma JM, Xin Y.
Quantitation and detection of deletion in tumor mitochondrial
DNA
by microarray technique. Zhonghua
Zhongliu Zazhi 2004; 26: 10-13
12
Fouts RL, Sandusky GE, Zhang S, Eckert GJ, Koch MO,
Ulbright TM, Eble JN, Cheng L. Down-regulation of
fragile histidine triad
expression in prostate carcinoma. Cancer 2003; 97:
1447-1452
13
Sukosd F, Kuroda N, Beothe T, Kaur AP, Kovacs G.
Deletion of chromosome 3p14.2-p25 involving the VHL and
FHIT genes in conventional
renal cell carcinoma. Cancer Res 2003; 63: 455-457
14
Baffa R, Veronese ML, Santoro R, Mandes B, Palazzo JP,
Rugge M, Santoro E, Croce CM, Huebner K. Loss of
FHIT expression in gastric
carcinoma. Cancer Res 1998; 58: 4708-4714
15
Huiping C, Kristjansdottir S, Bergthorsson JT,
Jonasson JG, Magnusson J, Egilsson V, Ingvarsson S. High
frequency
of LOH, MSI and abnormal
expression of FHIT in gastric cancer. Eur J Cancer 2002; 38:
728-735
16
Ohta M, Inoue H, Cotticelli MG, Kastury K, Baffa R,
Palazzo J, Siprashvili Z, Mori M, McCue P, Druck T, Croce
CM, Huebner K. The FHIT gene,
spanning the chromosome 3p14.2 fragile site and renal
carcinoma-associated t
(3; 8) breakpoint, is abnormal
in digestive tract cancers. Cell 1996; 84: 587-597
17
Chang KW, Kao SY, Tzeng RJ, Liu CJ, Cheng AJ, Yang SC,
Wong YK, Lin SC. Multiple molecular alterations of FHIT
in betel-associated oral
carcinoma. J Pathol 2002; 196: 300-306
18
An Q, Liu Y, Huang J. Comparison of tumor suppressor
gene deletion between squamous cell carcinoma
and adenocarcinoma lung cancer
in Chinese. Zhonghua Zhongliu Zazhi 2001; 23: 470-472
19
Ko JY, Lee TC, Hsiao CF, Lin GL, Yen SH, Chen KY,
Hsiung CA, Chen PJ, Hsu MM, Jou YS. Definition of three
minimal deleted regions by
comprehensive allelotyping and mutational screening of FHIT,
p16(INK4A), and p19
(ARF) genes in nasopharyngeal
carcinoma. Cancer 2002; 94: 1987-1996
20
Wistuba II, Ashfaq R, Maitra A, Alvarez H, Riquelme E,
Gazdar AF. Fragile histidine triad gene abnormalities in
the pathogenesis of gallbladder
carcinoma. Am J Pathol 2002; 160: 2073-2079
21
Andachi H, Yashima K, Koda M, Kawaguchi K, Kitamura A,
Hosoda A, Kishimoto Y, Shiota G, Ito H, Makino M, Kaibara
N, Kawasaki H, Murawaki Y.
Reduced Fhit expression is associated with mismatch repair
deficiency in human
advanced colorectal carcinoma. Br
J Cancer 2002; 87: 441-445
22
Zhao P, Lu Y, Hu Y, Zhong M, Li Z, Li X. Loss of
fragile histidine triad expression in colorectal carcinoma.
Zhonghua Binglixue Zazhi
2002; 31: 124-127
23
Otterson GA, Xiao GH, Geradts J, Jin F, Chen WD,
Niklinska W, Kaye FJ, Yeung RS. Protein expression and
functional analysis of the FHIT
gene in human tumor cells. J Natl Cancer Inst 1998; 90:
426-432
24
Etoh T, Kanai Y, Ushijima S, Nakagawa T, Nakanishi Y,
Sasako M, Kitano S, Hirohashi S. Increased
DNA methyltransferase 1 (DNMT1)
protein expression correlates significantly with poorer tumor
differentiation
and frequent DNA
hypermethylation of multiple CpG islands in gastric cancers. Am J
Pathol 2004; 164: 689-699
25
Kijima Y, Ishigami S, Hokita S, Koriyama C, Akiba S,
Eizuru Y, Aikou T. The comparison of the prognosis
between Epstein-Barr virus (EBV)-positive
gastric carcinomas and EBV-negative ones. Cancer Lett 2003; 200:
33-40
26
Shibata DK. Epstein-Barr virus and gastric carcinoma. Jpn
J Cancer Res 1996; 87: Inside front cover
27
Sudo M, Chong JM, Sakuma K, Ushiku T, Uozaki H, Nagai H,
Funata N, Matsumoto Y, Fukayama M.
Promoter
hyperm-ethylation of E-cadherin and its abnormal expression in
Epstein-Barr virus-associated
gastric carcinoma. Int J
Cancer 2004; 109: 194-199
28
Zur Hausen A, Crusius JB, Murillo LS, Alizadeh BZ,
Morre SA, Meijer CJ, van den Brule AJ, Pena AS. IL-1B
promoter polymorphism and
Epstein-Barr virus in Dutch patients with gastric carcinoma. Int
J Cancer 2003;
107: 866-867
29
Thompson MP, Kurzrock R. Epstein-Barr virus and
cancer. Clin Cancer Res 2004; 10: 803-821
30
Chang MS, Lee HS, Kim HS, Kim SH, Choi SI, Lee BL, Kim
CW, Kim YI, Yang M, Kim WH. Epstein-Barr virus
and microsatellite instability
in gastric carcinogenesis. J Pathol 2003; 199: 447-452
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