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World J Gastroenterol. Oct 15, 2000; 6(5): 750-753
Published online Oct 15, 2000. doi: 10.3748/wjg.v6.i5.750
Infrequent p53 gene mutation and expression of the cardia adenocarcinomas from a high-incidence area of Southwest China
Xiu Jie Wang, Shu Lan Yuan, Chang Ping Li, Naoko Iida, Hideaki Oda, Shigetoshi Aiso, Takatoshi Ishikawa
Xiu Jie Wang, Shu Lan Yuan, Institute of Cancer Research, Cancer Center, The First University Hospital of West China University of Medical Sciences, Chengdu 610041, Sichuan Province, China
Chang Ping Li, Department of Gastroenterology, Affiliated Hospital, Luzhou Medical College, 646000, Sichuan Province, China
Naoko Iida, Hideaki Oda, Shigetoshi Aiso, Takatoshi Ishikawa, Department of Molecular Pathology, Faculty of Medicine, the University of Tokyo, HongoTokyo 113, Japan
Xiu Jie Wang, graduated from West China University of Medical Sciences in 1982, now associate professor of oncology, engaged in the researches of etiol ogy and mechanisms of carcinogenesis of cancers, screening and exploiting anticancer drugs, having more than 20 papers published.
Author contributions: All authors contributed equally to the work.
Correspondence to: Xiu Jie Wang, Institute of Cancer Research, Cancer Center, The First University Hospital of West China University of Medical Sciences, Chengdu 610041, Sichuan Province, China.
Telephone: 0086-28-5501281 Fax: 0086-28-5583252
Received: April 3, 2000
Revised: June 20, 2000
Accepted: July 31, 2000
Published online: October 15, 2000

Key Words: cardia adenocarcinoma/etiology, protein P53, gene expression, mutation, genes p53, polymerase chain reaction, DNA, risk factors


Adenocarcinomas of the cardia are the lesions arising from the proximal stomach or within 3 cm of the gastroesophageal junction[1,2]. These cancers tended to be advanced at the time of presentation, usually with poor prognosis[2]. In recent decade, the incidence of adenocarcinoma of gastric cardia and esophagus are increasing steadily, while there has been a decrease in the proportion of the cancers arising from the distal stomach[3-8]. The biological and epidemiological features of the cardia adenocarcinoma were distinct from those arising from the distal stomach[9,10]. The specific etiologic factors involved in the increasing incidence remained unresolved[1,5-10].

Significantly higher levels of DNA aneuloidy[11,12], p53 protein expression[1,12-17] and mutations[1,18] have been reported in gastric cardia tumors, compared with tumors arising in the gastric antrum. p53 expression may be used as a marker in the early detection of cardia adenocarcinoma[2], mutations of p53 gene at specific codons in human cancers may be an indication of specific exposure or genomic susceptibility[14,15,19-22], and may serve as a reporter gene reflecting exposure to specific carcinogen[14,21-23]. The previous studies[1,11-23]. Suggested that the mutation and functional inactivation of p53 gene might play some important roles in the carcinogenesis of cardia adenocarcinomas etiologically.

In this study, the p53 gene mutation spectrum and protein overexpression were investigated in the cardia adenocarcinoma from a high-incidence area of Southwest China, comparison of mutation spectra was made with those in cardia adenocarcinomas from other regions, some clues may be drawn to the etiology and carcinogenesis of cardia adenocarcinomas in the local area.

Patients and samples

All 20 cases of cardia adenocarcinoma specimens were collected from patients surgically treated in Yanting County Cancer Hospital of Sichuan Province in Southwest China. Of all 20 patients, 17 (85%) were male, 3 (15%) were female, age ranged from 46 to 69 years (mean, 54.9 years). None had received any treatment before the operation; all patients were diagnosed as having cardia adenocarcinoma arising within the gastroesophageal junction[2]. None was associated with Barrett’s esophageal epithelium. All tissue specimens were routinely processed, formalin-fixed, and paraffin-embedded. Paraffin sections were stained with hematoxylin and eosin (HE) for histopathological examination, and were used for DNA isolation and detection of p53 protein by immunohistochemi cal staining.

DNA isolation

The paraffin embedded blocks were sectioned at 10 μm, attached to glass slides and used for genomic DNA isolation by means of Pinpoint Slide DNA Isolation System (Zymo Research, USA), according to the manuf acturer’s instructions. Briefly, a 1 mm2 area of cancer tissue with few other cells except cancer cells was localized on HE staining slides under microscopy in each case; the 10 μm slides were de-paraffinized, rehydrated through graded alcohols and air dried. With reference to the HE staining slides of the same case, the PP solution was applied to the localized area of each case. After air dry for 30-45 min, the PP solution embedded tissues were peeled and removed from the glass slides, and added into the tubes containing 50 µL extraction buffer and 5 µL proteinase K solution, then incubated at 55 °C for 4 h, heated at 95 °C for 10 min. The isolated DNA was further purified with DNA binding buffer and mini-spin column and PP wash buffer supplied by the manufacturer.

PCR and asymmetric PCR amplification

To amplify the DNA segments of exons 5-8 of p53, 100 ng-200 ng aliquots of template DNA were added in a total volume of 25 µL- PCR reaction mixture containing 1 × PCR buffer, 0.2 mM of each dNTP (PE Applied Biosy stems), 1 µm of each primer and 2.0 units of AmpliTaq Gold DNA polymerase (Perkin Elmer). Initial denaturation at 94 was performed for 9 min, followed by 50 cycles of 30 s at 94 °C, 30 s at 52 °C or 58 °C (depending on the primers), 45 s at 72 °C and a final extension of 7 min at 72 °C. The primers used in this study covered the portions of exons 5-8 of the human p53 gene as described before[24].

Twenty microliters of PCR products were run on a 2.0% agarose gel for examining the specificity of PCR reaction and DNA recovery, the specific bands were cut, recovered by Sprec-DNA Recovery Filter Tubes (Takara Biomedical, Japan), and purified according to the manufacturer’s instruction. The recovered DNA fragments were used as templates for asymmetric PCR amplification. The two single-stranded DNA fragment of each exon were amplified with asymmetric PCR by using only one primer, respectively, except of the doubled primer, the conditions of asymmetric PCR were the same as those of the first PCR amplification.

DNA sequencing

Asymmetric PCR products were purified by alcohol precipitation, one fourth of purified product was used for DNA sequencing. DNA sequencing was performed by dideoxynucleotide method using the Thermo Sequenase cycle sequencing kit (Amersham, Life Science) and γ32p-ATP (Amersham, Pharmacia Biotech). The sequence ladder was resolved in 7.0 M urea and 6% polyacrylamide gel. After electrophoresis, the gel was dried in the Bio-Rad gel dryer before exposure to X-ray film for 6-12 h at -70 °C. When base changes were identified repeated sequencing of the same or complementary DNA strand was performed for confirmation[19].

Immunohistochemical analysis of p53 proteins

P53 protein was detected immunohistochemically with the avidin-biotin-peroxidase method[25]. Briefly, tissue sections were de-paraffinized and re-hydrated through graded alcohols. Antigen retrieval was performed by microwave oven heating in 0.1 mM citrate buffer (pH6). Then, endogenous peroxidase activity was blocked with 3% H2O2, and after treatment with normal serum, the sections were incubated with CM1 polyclonal rabbit p53 antibody (Novocastra, Newcastle upon Tyne, UK) at a dilution of 1:500, overnight at 4 °C, with biotylated second antibody 20 min, and with avidin-biotin-peroxidase complex 20 min at room temperature. Subsequently, the sections were subjected to color reaction with 0.02% 3, 3 diaminobenzidine tetrahydrochloride containing 0.005% H2O2 in PBS (pH7.4), and were counterstained with hematoxylin lightly. In each staining run, a known p53 positive sample of colon cancer was added as a positive control, and a section of the same colon cancer tissue incubated in PBS instead of CM1 was included as a negative control.

Approximate percentage of p53 positive tumor cell nuclei in carcinoma were as sessed and scored as follows: negative (-), < 10% (+), 10%-50% (++), > 50% (+++); The intensity of staining in p53 positive cell nuclei was compared with the negative control and scored as follows: negative (-), weak (+), moderate (++), strong (+++)[25].

p53 mutations in cardia adenocarcinoma

In all 20 cases of cardia adenocarcinomas, only 2 mutations (10%, 2/20) of p53 gene were detected in 2 cases. There were ATC-ACC, T to C transition in one occurred at codon 195 in exon 6 and CGC-AGC, C to A transversion in another at codon 283 in exon 8. Two were missense mutations. A representative mutation is shown in Figure 1.

Figure 1
Figure 1 Results of sequence analysis of the p53 gene in the cardia adenocarcinomas from a high incidence area of Southwest China, case 96-236 showed a ATC-to ACC mutation at codon 195 of exon 6.
p53 overexpression in cardia adenocar-cinomas

All immunostainings for p53 protein were confined to the cell nuclei (Figure 2), the positive cell number varied from 10% to more than 50%; The intensity of staining ranged from moderate to strong. Seven out of 20 (35%, 7/20) were detected with p53 protein overexpression.

Figure 2
Figure 2 Immunoreactivity of p53 protein of cardia a denocarcinoma, p53 protein was located in the nuclei of cancer cells, most cancer cells were positive for p53 protein. ABC × 20

In addition, in 2 cases with p53 gene mutations, one was p53 protein-positive (96-236, codon 195: ATC-ACC); one was negative for p53 protein (96-237, codon 283: CGC-AGC). All paracancerous normal tissues were p53-negative. In 5 cancers with lymph node metastasis, 2 were p53-positive of both cancer and lymph node, and 3 were p53-negative in both tissues. The positive cases with p53 gene mutations and/or p53 protein overexpression are summarized in Table 1.

Table 1 The positive cases with p53 gene mutation and/or p53 protein overexpression in cardia adenocarcinomas.
Patient No.ExonCodonNucleotide changeAmino acid changep53 protein expression

The present study investigated the p53 gene mutation and protein expression in a series of 20 cases of cardia adenocarcinomas from a high incidence area of Southwest China, the rates of p53 mutation and protein expression were lower than those reported previously.

There were less reports of p53 mutation and protein expression in cardia aden ocarcinomas than those in other cancers (http:/ htm)[26], such as, hepatocellular carcinoma[27-29], esophageal cancer and gastric cancer[14,20-22]. Li et al[30] detected p53 mutations in 3 out of 4 cardia adenocarcinomas (3/4), 6 mutations were identified in exons 5-8 of p53 gene in 6 out of 14 cardia adenocarcinomas (6/14, 42.9%) from Linxian, China, 3 were missense mutations, and 3 were non-sense mutations[18]. Recently, a high p53 mutation rate (63%, 26/41) in cardia adenocarcinomas from North Ireland was reported[1]. As for the p53 protein expression, the positive rates reported in cardia adenocarcinoma were 59% (24/41)[1], 44% (11/25)[2], 56% (20/ 36)[12], and 76.5% (13/17)[13], respectively. These results suggested that p53 mutation and expression played an important role in carcinogenesis of cardia adenocarcinoma, and p53 gene mutations reflected exposures to specific carcinogens in the environment[14,19,21-23].

Conversely, in our series, only 2 cases of p53 gene mutation (10%) and 7 cases of p53 protein expression (35%) were detected in 20 cardia adenocarcinomas from a high incidence area of China. It had been proposed that the comparison of p53 gene mutation spectra in tumors of different origin might reveal similarities or differences concerning the endogenous and exogenous molecular processes contributing to tumor development[24], and might reflect site-specific difference (cardia or antrum) or regional exposure to particular environmental agents[31]. The results in this study suggested that p53 gene mutation might play some role in some subset of cardia adenocarcinomas, but, it is not the major causation in carcinogenesis of gastric cardia in local area, or the risk factors in the local environment are different from those in other regions.

To the best of our knowledge[1,18,26,30], the two mutations detected in the present study were rare in cardia adenocarcinomas. Mutation of p53 gene at codon 195 from ATC to ACC was reported in ovarian cancer[32], brain tumors[33], lung cancers[34,35], and adenocarcinoma of Barrett’s esophagus[36], etc.[26]; Mutation at codon 283 was of polymorphism in previous studies: It was from CGC to TGC in hepatocellular carcinoma[37] and colorectal cancers[38], CGC to CTC in ovarian tumor[39], CGC to GGC in lung cancer[40,41], etc[26]. But, in this series, the mutation at codon 283 was from CGC to AGC, C:G-A:T transversion, no such a mutation was reported previously. It was further suggest ed that the environmental risk factors and their mechanism of actions in local area were different from those in other regions[1,18,30].

The disconcordance between p53 protein expression and p53 gene mutation was noted in many other studies[1,25,35], one case with p53 gene mutation was negative for p53 protein immunohistochemical staining in this study, since the frameshifts or non-sense mutations in the coding sequences of the gene might result in truncated or unstable forms, even non-expression[25]. No mutations in exons 5-8 were detected in other 6 cases with positive p53 protein, the possibilities to account for this apparent disconcordance might be: Firstly, the missense mutation lay in the region of the gene not screened in this study. Although p53 gene mutations occurred frequently in the so-called ‘hot-spot’ region of exons 5-8[35], a review of 50 studies that carried out sequencing of the entire coding region of p53 gene reported that 13% up to 30% of missense mutations were located outside exons 5-8[23]; Another possibility was that the mechanism other than mutations resulted in inactivation and stabilization of p53 protein. Binding to viral oncop roteins, e.g. HPV E6, and cellular oncoproteins, e.g. mdm2, had been shown to result in p53 stabilization and in the inactivation of wild-type function[41,42]. Our previous studies indicated that there was a high prevalence of HPV16 of esophageal cancer patients and health population in this high incidence area[43,44]. In these instances, p53 overexpression represented the fun ctional, but not the structural, inactivation of p53 gene[1].

We conducted a preliminary investigation of p53 gene mutation and p53 protein expression in 20 cases of cardia adenocarcinomas from a high incidence area in Southwest China, to elucidate the etiology and carcinogenesis of cardia adenocarcinoma in the local area. The low p53 gene mutation and expression rates, and different mutation spectrum suggested that p53 gene mutation and functional inactivation might play some roles in the subset of cardia adenocarcinomas in this high incidence area. Besides p53 gene abnormalities, there might be some other environmental risk factors and other genetic abnormalities contributing to the high incidence of cardia adenocarcinomas in this area, which deserves further investigation.


Edited by Wu XN Proofread by Zhu LH and Ma JY

1.  Gleeson CM, Sloan JM, McManus DT, Maxwell P, Arthur K, McGuigan JA, Ritchie AJ, Russell SE. Comparison of p53 and DNA content abnormalities in adenocarcinoma of the oesophagus and gastric cardia. Br J Cancer. 1998;77:277-286.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 59]  [Cited by in F6Publishing: 69]  [Article Influence: 2.4]  [Reference Citation Analysis (0)]
2.  Iannettoni MD, Lee SS, Bonnell MR, Sell TL, Whyte RI, Orringer MB, Beer DG. Detection of Barrett's adenocarcinoma of the gastric cardia with sucrase isomaltase and p53. Ann Thorac Surg. 1996;62:1460-1465; discussion 1460-1465.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 5]  [Cited by in F6Publishing: 5]  [Article Influence: 0.2]  [Reference Citation Analysis (0)]
3.  Powell J, McConkey CC. Increasing incidence of adenocarcinoma of the gastric cardia and adjacent sites. Br J Cancer. 1990;62:440-443.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 264]  [Cited by in F6Publishing: 292]  [Article Influence: 8.0]  [Reference Citation Analysis (0)]
4.  Blot WJ, Devesa SS, Kneller RW, Fraumeni JF. Rising incidence of adenocarcinoma of the esophagus and gastric cardia. JAMA. 1991;265:1287-1289.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 1271]  [Cited by in F6Publishing: 1285]  [Article Influence: 39.7]  [Reference Citation Analysis (0)]
5.  Sampliner RE. Adenocarcinoma of the esophagus and gastric cardia: is there progress in the face of increasing cancer incidence? Ann Intern Med. 1999;130:67-69.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 14]  [Cited by in F6Publishing: 18]  [Article Influence: 0.6]  [Reference Citation Analysis (0)]
6.  Wang XJ, Yuan SL, Xiao L, Wang XH, Wang CJ. The expression of c-src gene in the carcinogenesis process of human cardia adenocarcinoma. World J Gastroenterol. 1999;5:488-491.  [PubMed]  [DOI]  [Cited in This Article: ]
7.  Wang XJ, Wang XH, Wang CJ, Huang GQ, Xiao HY. An immunohistochemical obse rvation of src gene product in cardiac carcinoma. Zhongguo Zhongliu Linchuang. 1996;23:319-324.  [PubMed]  [DOI]  [Cited in This Article: ]
8.  He LJ, Wu M. The distribution of esophageal and cardiac carcinoma and precanceous of 2238. World J Gastroentero. 1998;4:100.  [PubMed]  [DOI]  [Cited in This Article: ]
9.  Sidoni A, Lancia D, Pietropaoli N, Ferri I. Changing patterns in gastric carcinoma. Tumori. 1989;75:605-608.  [PubMed]  [DOI]  [Cited in This Article: ]
10.  Gao SS, Zhou Q, Li YX, Bai YM, Zheng ZY, Zou JX, Liu G, Fan ZM, Qi YJ, Zhao X. Comparative studies on epithelial lesions at gastric cardia and pyloric antrum in subjects from a high incidence area for esophageal cancer in Henan, China. World J Gastroenterol. 1998;4:332-333.  [PubMed]  [DOI]  [Cited in This Article: ]
11.  Johnson H, Belluco C, Masood S, Abou-Azama AM, Kahn L, Wise L. The value of flow cytometric analysis in patients with gastric cancer. Arch Surg. 1993;128:314-317.  [PubMed]  [DOI]  [Cited in This Article: ]
12.  Fléjou JF, Muzeau F, Potet F, Lepelletier F, Fékété F, Hénin D. Overexpression of the p53 tumor suppressor gene product in esophageal and gastric carcinomas. Pathol Res Pract. 1994;190:1141-1148.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 20]  [Cited by in F6Publishing: 23]  [Article Influence: 0.7]  [Reference Citation Analysis (0)]
13.  Shun CT, Wu MS, Lin JT, Chen SY, Wang HP, Lee WJ, Wang TH, Chuang SM. Relationship of p53 and c-erbB-2 expression to histopathological features, Helicobacter pylori infection and prognosis in gastric cancer. Hepatogastroenterology. 1997;44:604-609.  [PubMed]  [DOI]  [Cited in This Article: ]
14.  Wang LD, Zhou Q, Zhang YC, Li XF, Wang WP, He L, Gao SS, Li YX. P53 alterations and cell proliferation in esophageal epithelia among subjects from high and low incidence areas of esophageal cancer. China Natl J New Gastroenterol. 1997;3:80.  [PubMed]  [DOI]  [Cited in This Article: ]
15.  Qiao GB, Han CL, Jiang RC, Sun CS, Wang Y, Wang YJ. Overexpression of P53 and its risk factors in esophageal cancer in urban areas of Xi'an. World J Gastroenterol. 1998;4:57-60.  [PubMed]  [DOI]  [Cited in This Article: ]
16.  Yu GQ, Zhou Q, Ivan D, Gao SS, Zheng ZY, Zou JX, Li YX, Wang LD. Changes of p53 protein blood level in esophageal cancer patients and normal subjects from a high incidence area in Henan, China. World J Gastroenterol. 1998;4:365-366.  [PubMed]  [DOI]  [Cited in This Article: ]
17.  Zhou Q, Wang LD, Gao SS, Li YX, Zhao X, Wang LX. p53 immunostaining positive cells correlated positively with S phase cells as measured by BrdU in the esophageal precancerous lesions from the subjects at high incidence area for esophageal cancer in northern China. World J Gastroentero. 1998;4:106-107.  [PubMed]  [DOI]  [Cited in This Article: ]
18.  Liang YY, Estève A, Martel-Planche G, Takahashi S, Lu SH, Montesano R, Hollstein M. p53 mutations in esophageal tumors from high-incidence areas of China. Int J Cancer. 1995;61:611-614.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 21]  [Cited by in F6Publishing: 22]  [Article Influence: 0.8]  [Reference Citation Analysis (0)]
19.  Shiao YH, Palli D, Buzard GS, Caporaso NE, Amorosi A, Saieva C, Fraumeni JF, Anderson LM, Rice JM. Implications of p53 mutation spectrum for cancer etiology in gastric cancers of various histologic types from a high-risk area of central Italy. Carcinogenesis. 1998;19:2145-2149.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 11]  [Cited by in F6Publishing: 16]  [Article Influence: 0.4]  [Reference Citation Analysis (0)]
20.  Wang LD, Yang WC, Zhou Q, Xing Y, Jia YY, Zhao X. Changes of p53 and Waf1p21 and cell proliferation in esophageal carcinogenesis. China Natl J New Gastroenterol. 1997;3:87-89.  [PubMed]  [DOI]  [Cited in This Article: ]
21.  Casson AG. Molecular biology of Barrett's esophagus and esophageal cancer: role of p53. World J Gastroenterol. 1998;4:277-279.  [PubMed]  [DOI]  [Cited in This Article: ]
22.  Wang LD, Zhou Q, Wei JP, Yang WC, Zhao X, Wang LX, Zou JX, Gao SS, Li YX, Yang C. Apoptosis and its relationship with cell proliferation, p53, Waf1p21, bcl-2 and c-myc in esophageal carcinogenesis studied with a high-risk population in northern China. World J Gastroenterol. 1998;4:287-293.  [PubMed]  [DOI]  [Cited in This Article: ]
23.  Greenblatt MS, Bennett WP, Hollstein M, Harris CC. Mutations in the p53 tumor suppressor gene: clues to cancer etiology and molecular pathogenesis. Cancer Res. 1994;54:4855-4878.  [PubMed]  [DOI]  [Cited in This Article: ]
24.  Oda H, Nakatsuru Y, Imai Y, Sugimura H, Ishikawa T. A mutational hot spot in the p53 gene is associated with hepatoblastomas. Int J Cancer. 1995;60:786-790.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 16]  [Cited by in F6Publishing: 16]  [Article Influence: 0.6]  [Reference Citation Analysis (0)]
25.  Suwiwat S, Oda H, Shimizu Y, Ishikawa T. Prevalence of p53 mutations and protein expression in esophageal cancers in southern Thailand. Int J Cancer. 1997;72:23-26.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in F6Publishing: 1]  [Reference Citation Analysis (0)]
26.  Hainaut P, Hernandez T, Robinson A, Rodriguez-Tome P, Flores T, Hollstein M, Harris CC, Montesano R. IARC Database of p53 gene mutations in human tumors and cell lines: updated compilation, revised formats and new visualisation tools. Nucleic Acids Res. 1998;26:205-213.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 315]  [Cited by in F6Publishing: 343]  [Article Influence: 12.6]  [Reference Citation Analysis (0)]
27.  Wang D, Shi JQ. Overexpression and mutations of tumor suppressor gene p53 in hepatocellular carcinoma. China Natl J New Gastroenterol. 1996;2:161-164.  [PubMed]  [DOI]  [Cited in This Article: ]
28.  Deng ZL, Ma Y. Aflatoxin sufferer and p53 gene mutation in hepatocellular carcinoma. World J Gastroenterol. 1998;4:28-29.  [PubMed]  [DOI]  [Cited in This Article: ]
29.  Peng XM, Yao CL, Chen XJ, Peng WW, Gao ZL. Codon 249 mutations of p53 gene in non-neoplastic liver tissues. World J Gastroenterol. 1999;5:324-326.  [PubMed]  [DOI]  [Cited in This Article: ]
30.  Li HC, Lu SX. [Mutation of p53 gene in human cancers of the esophagus and gastric cardia]. Zhonghua Zhongliu Zazhi. 1994;16:172-176.  [PubMed]  [DOI]  [Cited in This Article: ]
31.  Hongyo T, Buzard GS, Palli D, Weghorst CM, Amorosi A, Galli M, Caporaso NE, Fraumeni JF, Rice JM. Mutations of the K-ras and p53 genes in gastric adenocarcinomas from a high-incidence region around Florence, Italy. Cancer Res. 1995;55:2665-2672.  [PubMed]  [DOI]  [Cited in This Article: ]
32.  Righetti SC, Della Torre G, Pilotti S, Ménard S, Ottone F, Colnaghi MI, Pierotti MA, Lavarino C, Cornarotti M, Oriana S. A comparative study of p53 gene mutations, protein accumulation, and response to cisplatin-based chemotherapy in advanced ovarian carcinoma. Cancer Res. 1996;56:689-693.  [PubMed]  [DOI]  [Cited in This Article: ]
33.  del Arco A, García J, Arribas C, Barrio R, Blázquez MG, Izquierdo JM, Izquierdo M. Timing of p53 mutations during astrocytoma tumorigenesis. Hum Mol Genet. 1993;2:1687-1690.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 15]  [Cited by in F6Publishing: 16]  [Article Influence: 0.5]  [Reference Citation Analysis (0)]
34.  Ambs S, Bennett WP, Merriam WG, Ogunfusika MO, Oser SM, Khan MA, Jones RT, Harris CC. Vascular endothelial growth factor and nitric oxide synthase expression in human lung cancer and the relation to p53. Br J Cancer. 1998;78:233-239.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 93]  [Cited by in F6Publishing: 102]  [Article Influence: 3.7]  [Reference Citation Analysis (0)]
35.  Tomizawa Y, Kohno T, Fujita T, Kiyama M, Saito R, Noguchi M, Matsuno Y, Hirohashi S, Yamaguchi N, Nakajima T. Correlation between the status of the p53 gene and survival in patients with stage I non-small cell lung carcinoma. Oncogene. 1999;18:1007-1014.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 60]  [Cited by in F6Publishing: 60]  [Article Influence: 2.5]  [Reference Citation Analysis (0)]
36.  Hamelin R, Fléjou JF, Muzeau F, Potet F, Laurent-Puig P, Fékété F, Thomas G. TP53 gene mutations and p53 protein immunoreactivity in malignant and premalignant Barrett's esophagus. Gastroenterology. 1994;107:1012-1018.  [PubMed]  [DOI]  [Cited in This Article: ]
37.  Kubicka S, Trautwein C, Schrem H, Tillmann H, Manns M. Low incidence of p53 mutations in European hepatocellular carcinomas with heterogeneous mutation as a rare event. J Hepatol. 1995;23:412-419.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 22]  [Cited by in F6Publishing: 23]  [Article Influence: 0.8]  [Reference Citation Analysis (0)]
38.  Baker SJ, Preisinger AC, Jessup JM, Paraskeva C, Markowitz S, Willson JK, Hamilton S, Vogelstein B. p53 gene mutations occur in combination with 17p allelic deletions as late events in colorectal tumorigenesis. Cancer Res. 1990;50:7717-7722.  [PubMed]  [DOI]  [Cited in This Article: ]
39.  Skomedal H, Kristensen GB, Abeler VM, Børresen-Dale AL, Tropé C, Holm R. TP53 protein accumulation and gene mutation in relation to overexpression of MDM2 protein in ovarian borderline tumours and stage I carcinomas. J Pathol. 1997;181:158-165.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in F6Publishing: 1]  [Reference Citation Analysis (0)]
40.  Chung KY, Mukhopadhyay T, Kim J, Casson A, Ro JY, Goepfert H, Hong WK, Roth JA. Discordant p53 gene mutations in primary head and neck cancers and corresponding second primary cancers of the upper aerodigestive tract. Cancer Res. 1993;53:1676-1683.  [PubMed]  [DOI]  [Cited in This Article: ]
41.  Top B, Mooi WJ, Klaver SG, Boerrigter L, Wisman P, Elbers HR, Visser S, Rodenhuis S. Comparative analysis of p53 gene mutations and protein accumulation in human non-small-cell lung cancer. Int J Cancer. 1995;64:83-91.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 51]  [Cited by in F6Publishing: 59]  [Article Influence: 1.8]  [Reference Citation Analysis (0)]
42.  Wu X, Bayle JH, Olson D, Levine AJ. The p53-mdm-2 autoregulatory feedback loop. Genes Dev. 1993;7:1126-1132.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 1257]  [Cited by in F6Publishing: 1366]  [Article Influence: 41.9]  [Reference Citation Analysis (0)]
43.  Wang XJ, Wang CJ, Wang XH, Tao DM, Xiao HY. Relationship between human papillomavirus infection and the development of esophageal carcinoma. Zhongguo Zhongliu Linchuang. 1996;23:761-764.  [PubMed]  [DOI]  [Cited in This Article: ]
44.  Wang XJ, Wang XH, Wang CJ, Tao DM, Xiao HY. Etiologic relationship between human papillomavirus and esophageal cancer. Zhongguo Zhongliu Linchuang. 1998;25:270.  [PubMed]  [DOI]  [Cited in This Article: ]