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1.
Cancer Detect Prev ; 25(3): 237-44, 2001.
Article in English | MEDLINE | ID: mdl-11425265

ABSTRACT

In order to identify the significant allelic loss involving the gastric adenoma-carcinoma sequence, we used 49 genome-wide microsatellite markers in an allelotype study of 30 cases of stomach resections that harbored both adenomas and carcinomas. Frequent loss of heterozygosity was demonstrated on 12q (53.3%), 2p (50.0%), and 18p (50.0%) in adenomas and on 8q (80.0%), 2p (70.0%), 18p (66.7%), and 17p (61.9%) in carcinomas. Significant difference in the loss of heterozygosity rate between the adenoma and the carcinoma was noted on 17p. Our results suggested that the critical target of loss of heterozygosity in gastric adenomacarcinoma sequences may be the p53 gene on 17p.


Subject(s)
Adenoma/genetics , Carcinoma/genetics , Cell Transformation, Neoplastic , Chromosomes, Human, Pair 17/genetics , Loss of Heterozygosity , Stomach Neoplasms/genetics , Adenoma/pathology , Aged , Alleles , Carcinoma/pathology , DNA, Neoplasm/genetics , Female , Humans , Male , Middle Aged , Stomach Neoplasms/pathology
2.
Int J Cancer ; 95(2): 108-13, 2001 Mar 20.
Article in English | MEDLINE | ID: mdl-11241321

ABSTRACT

beta-catenin serves not only as a structural component of the E-cadherin-mediated cell-cell adhesion system, but also as a signaling molecule of the Wnt/wingless pathway. Deregulated expression of beta-catenin and mutations of the gene have been identified in a number of human malignancies. To determine the role of beta-catenin defects in stomach cancer, we investigated beta-catenin exon 3 mutations and altered protein expression in 77 primary gastric carcinomas and 11 cell lines. In addition, the immunohistochemical expression pattern of beta-catenin in 303 consecutive gastric cancers was determined and their relationships with clinicopathologic features and patient outcome were investigated. This study revealed 5% (4 of 77) tumors and 27% (3 of 11) cell lines with beta-catenin gene alteration, 6 missense mutations, and 1 interstitial deletion. These genetic changes were shown to correlate closely with nuclear localization of the protein (p = 0.001). In an immunohistochemical analysis, abnormal expressions of beta-catenin, such as nuclear accumulation and loss of membranous distribution, were detected in 27% (81 of 303) of tumors overall. These altered beta-catenin expressions were more commonly observed in 37% (58 of 158) diffuse type gastric carcinomas (p < 0.001). Loss of membranous beta-catenin staining was associated with poor survival (p = 0.045). In conclusion, our results demonstrate that beta-catenin mutations are common in gastric cancer cell lines but occur infrequently in gastric carcinoma tissues. These mutations are one of the causes of the nuclear accumulation of beta-catenin. Frequent abnormalities of beta-catenin expression in gastric carcinoma support the idea that both structural and signaling functions of the protein play a critical role in gastric carcinogenesis.


Subject(s)
Cytoskeletal Proteins/biosynthesis , Cytoskeletal Proteins/genetics , Mutation , Stomach Neoplasms/genetics , Stomach Neoplasms/metabolism , Trans-Activators , Adolescent , Adult , Age Factors , Aged , Aged, 80 and over , Carcinoma/genetics , Carcinoma/metabolism , Carcinoma/mortality , Cell Nucleus/metabolism , DNA Mutational Analysis , Exons , Female , Follow-Up Studies , Gastric Mucosa/metabolism , Gene Deletion , Humans , Immunohistochemistry , Male , Middle Aged , Mutation, Missense , Point Mutation , Sex Factors , Signal Transduction , Stomach Neoplasms/mortality , Time Factors , Treatment Outcome , Tumor Cells, Cultured , beta Catenin
3.
Int J Cancer ; 91(5): 619-24, 2001 Mar 01.
Article in English | MEDLINE | ID: mdl-11267970

ABSTRACT

Synchronous gastric carcinomas are found in 4% to 10% of all gastric carcinomas, and the tumor multiplicity is believed to be related to genetic predisposition. To investigate the role of mismatch repair error in synchronous gastric carcinomas, we analyzed the microsatellite instability (MSI) status of 101 cancers from 48 gastrectomy specimens and compared them with 149 solitary gastric carcinomas. Multiple synchronous gastric carcinomas are characterized by slightly older age, predominance in males, early stage and lower lymph node metastasis. Among the 48 cases, 8 (18 lesions) were associated with a gastric adenoma (type I) and 40 (83 lesions) were not associated with a gastric adenoma (type II). The MSI+ rate was 50% in the type I and 8.4% in the type II synchronous gastric carcinomas (p < 0.001), while that of solitary gastric carcinomas was 9.4%. In addition, the frameshift mutation rates of the TGF-betaRII, BAX and hMSH3 genes in the type I synchronous carcinomas were higher than those in the type II synchronous carcinomas. These findings indicate that a defect in the mismatch repair system might play a role in the carcinogenesis of a minor subset of multiple gastric carcinomas associated with adenomas.


Subject(s)
Carcinoma/genetics , Microsatellite Repeats , Multidrug Resistance-Associated Proteins , Proto-Oncogene Proteins c-bcl-2 , Stomach Neoplasms/genetics , Trinucleotide Repeat Expansion , Adaptor Proteins, Signal Transducing , Adenoma/genetics , Age Factors , Aged , Alleles , Base Pair Mismatch , Carrier Proteins , DNA Repair , DNA-Binding Proteins/genetics , Female , Frameshift Mutation , Genetic Predisposition to Disease , Humans , Immunohistochemistry , Lymphatic Metastasis , Male , Microsatellite Repeats/genetics , Middle Aged , MutL Protein Homolog 1 , MutS Homolog 2 Protein , MutS Homolog 3 Protein , Mutation , Neoplasm Proteins/genetics , Neoplasms, Multiple Primary/genetics , Nuclear Proteins , Protein Serine-Threonine Kinases , Proto-Oncogene Proteins/genetics , Receptor, Transforming Growth Factor-beta Type II , Receptors, Transforming Growth Factor beta/genetics , Sex Factors , bcl-2-Associated X Protein
4.
Cancer Lett ; 164(1): 61-8, 2001 Mar 10.
Article in English | MEDLINE | ID: mdl-11166916

ABSTRACT

We tested three mononucleotide, 45 dinucleotide, and five tetranucleotide repeats in 30 gastric adenomas and 30 gastric carcinomas for microsatellite instability (MSI) in order to evaluate which microsatellites might indicate the MSI status in gastric neoplasms. Along with the increase in tested markers, the proportion of low-frequency MSI (MSI-L) tumors increased. On immunohistochemistry, MSI-L gastric neoplasms did not show any alteration in hMLH1 or hMSH2 protein expression, while most of the high-frequency MSI (MSI-H) tumors did show alterations in the above mismatch repair proteins. The above findings suggested that MSI-L tumors cannot be distinguished from microsatellite stable tumors. Two mononucleotides, BAT25 and BAT26, were sufficient for the screening of MSI. An additional three dinucleotides, D17S786, D6S105 and D19S188, were also highly sensitive and specific in identifying MSI phenotype tumors.


Subject(s)
DNA-Binding Proteins , Microsatellite Repeats , Phenotype , Stomach Neoplasms/genetics , Adaptor Proteins, Signal Transducing , Adenoma/genetics , Adenoma/metabolism , Carcinoma/genetics , Carcinoma/metabolism , Carrier Proteins , Gastric Mucosa/metabolism , Genes, p53/genetics , Humans , Immunohistochemistry , MutL Protein Homolog 1 , MutS Homolog 2 Protein , Neoplasm Proteins/biosynthesis , Nuclear Proteins , Nucleotides/metabolism , Proto-Oncogene Proteins/biosynthesis , Sensitivity and Specificity , Stomach Neoplasms/metabolism , Trinucleotide Repeat Expansion
5.
Anticancer Res ; 20(5A): 2849-54, 2000.
Article in English | MEDLINE | ID: mdl-11062692

ABSTRACT

The MEN1 gene locus is known to be partly responsible for the tumorigenesis of sporadic gastric neuroendocrine tumors, but the genetic events that drive the neoplastic process of this tumor remain largely unknown. In order to screen the tumor suppressor genes associated with the tumorigenesis of gastric neuroendocrine tumors, 15 neuroendocrine carcinomas and three carcinoid tumors in the stomach were analyzed for loss of heterozygosity (LOH) using 22 microsatellite markers. In our study, the gastric neuroendocrine tumors showed a high rate of LOH in chromosomes 8p (82%), 15q (58%), 17p (57%), llp (50%), 12p (50%) and 13q (50%). The mean fractional allelic loss (FAL) was higher in the neuroendocrine carcinoma components than in the adenocarcinoma components (0.42 versus 0.33, respectively). In four cases, the adenocarcinoma components showed discordant LOH patterns from those of the neuroendocrine counterparts in half of the informative chromosomes analyzed. Comparably, the gastric neuroendocrine carcinomas exhibited a higher LOH frequency on 8p and a lower LOH on 7q than did the gastric adenocarcinomas. It is suggested that chromosome 8p is the possible location of the tumor suppressor genes associated with the tumorigenesis of gastric neuroendocrine tumors.


Subject(s)
Carcinoid Tumor/genetics , Carcinoma, Neuroendocrine/genetics , Genes, Tumor Suppressor , Loss of Heterozygosity , Neoplasm Proteins/genetics , Proto-Oncogene Proteins , Stomach Neoplasms/genetics , Aged , Carcinoid Tumor/classification , Carcinoid Tumor/pathology , Carcinoma, Large Cell/classification , Carcinoma, Large Cell/genetics , Carcinoma, Large Cell/pathology , Carcinoma, Neuroendocrine/classification , Carcinoma, Neuroendocrine/pathology , Carcinoma, Small Cell/classification , Carcinoma, Small Cell/genetics , Carcinoma, Small Cell/pathology , Female , Humans , Male , Middle Aged , Stomach Neoplasms/classification , Stomach Neoplasms/pathology
6.
Pathol Int ; 50(9): 690-5, 2000 Sep.
Article in English | MEDLINE | ID: mdl-11012981

ABSTRACT

Microsatellite instability (MSI) due to defective DNA mismatch repair (MMR) is a form of genomic instability underlying the tumorigenesis of various human neoplasms. To evaluate the roles of MSI in the pathogenesis of gastric carcinomas with squamous differentiation, 17 primary stomach cancer patients (15 adenosquamous and two squamous cell carcinomas) were examined for MSI frequency using five microsatellite markers and the criteria for MSI recommended by the National Cancer Institute Workshop. The molecular causes and consequences of MSI in these neoplasms were further researched through the immunohistochemistry of MMR proteins and the mutational analysis of cancer-associated genes targeted by MSI, respectively. Two of the 17 (12%) cases demonstrated MSI at the most examined loci and were classified as having high level MSI (MSI-H). These tumors also exhibited frame-shift mutations at mononucleotide repeats in the target genes, including TGFbetaRII, IGFIIR, BAX, and hMSH6. It is interesting to note that the mutations of the serine (AGC)13 repeats within the E2F-4 gene were found only in the squamous cell carcinoma portions of them, whereas such alterations were not detected in any of the adenocarcinomatous portions. This suggests that E2F-4 might be implicated in the transformation of adenocarcinoma into squamous cell carcinoma and further studies are needed to understand its role in squamous differentiation.


Subject(s)
Carcinoma, Adenosquamous/genetics , Carcinoma, Squamous Cell/genetics , DNA-Binding Proteins/genetics , Microsatellite Repeats , Stomach Neoplasms/genetics , Transcription Factors/genetics , Carcinoma, Adenosquamous/secondary , Carcinoma, Squamous Cell/secondary , DNA Primers/chemistry , DNA, Neoplasm/analysis , E2F4 Transcription Factor , Humans , Mutation , Stomach Neoplasms/pathology
7.
Surgery ; 128(1): 59-66, 2000 Jul.
Article in English | MEDLINE | ID: mdl-10876187

ABSTRACT

BACKGROUND: Hyperhomocysteinemia is recognized as a risk factor for atherosclerotic disease. However, the mechanism of homocysteine effects on smooth muscle cell proliferation, which is a hallmark of atherosclerosis, is unknown. The object of this study was to test the effects of homocysteine on smooth muscle cell proliferation, and to examine the mitogen-activated protein (MAP) kinases, extracellular signal-regulated protein kinase 1 and 2, that are known to be involved in cell proliferation. METHODS: For the proliferation study, bovine aortic smooth muscle cells (BASMC, 10, 000/well) were allowed to grow for 2 days before 2 mmol/L D,L -homocysteine was added for 2, 4, 6, and 8 days to simulate the clinical hyperhomocysteinemic condition. For the MAP kinase study, quiescent BASMC were exposed to 2 mmol/L D,L -homocysteine for 1.5, 5, 10, 20, 30, and 60 minutes, and the active forms of MAP kinase were detected with Western immunoblotting. The degree of phosphorylation of MAP kinase was determined by densitometry. RESULTS: D,L -homocysteine stimulated BASMC proliferation by 20% by day 8. MAP kinase phosphorylation was activated as much as six fold by D,L -homocysteine, with a peak at 30 minutes. PD98059, an inhibitor of MAP kinase phosphorylation, inhibited the homocysteine-induced MAP kinase phosphorylation and attenuated the increase in BASMC proliferation. CONCLUSIONS: These data are consistent with the hypothesis that D,L -homocysteine stimulation of BASMC proliferation involves MAP kinase activation.


Subject(s)
Homocysteine/pharmacology , Mitogen-Activated Protein Kinases/metabolism , Muscle, Smooth, Vascular/cytology , Muscle, Smooth, Vascular/enzymology , Animals , Aorta/cytology , Cattle , Cell Division/drug effects , Cells, Cultured , Dose-Response Relationship, Drug , Enzyme Activation/drug effects , Enzyme Inhibitors/pharmacology , Flavonoids/pharmacology , MAP Kinase Signaling System/drug effects , Mitogen-Activated Protein Kinase 1/metabolism , Mitogen-Activated Protein Kinase 3 , Phosphorylation
8.
Lab Invest ; 80(1): 57-64, 2000 Jan.
Article in English | MEDLINE | ID: mdl-10653003

ABSTRACT

Sixty-three cases of stomach resections harboring both adenoma and carcinoma were analyzed for microsatellite instability (MSI). The cases included 28 carcinomas arising from adenoma (Type I) and 35 carcinomas with separate adenoma (Type II). The results of MSI assessed by 49 markers were the same for BAT-26 instability. The incidence of MSI was 21% in gastric adenoma and 30% in gastric carcinoma, which is significantly higher than gastric carcinoma without associated adenoma (p < 0.01). Five of eight (63%) cases of multiple carcinomas associated with adenoma showed MSI+ in adenoma and in one or more carcinoma lesion(s). Eight of thirteen (62%) MSI+ adenomas were associated with carcinoma, whereas 20 of 50 (40%) MSI adenomas were associated with carcinoma. MSI+ adenomas of Type I showed a higher mutation rate of the TGF-beta RII gene than Type II (88% versus 40%). Gastric adenoma with TGF-beta RII gene mutation was more prone to transform into carcinoma (p = 0.03). This study revealed that gastric carcinoma arising from adenoma is frequently associated with a mismatch repair deficiency mechanism. In the gastric adenoma-carcinoma sequence, TGF-beta RII gene mutation occurred early in the adenoma stage and it persisted after malignant transformation.


Subject(s)
Adenoma/genetics , Carcinoma/genetics , Microsatellite Repeats , Stomach Neoplasms/genetics , Adenoma/pathology , Aged , Carcinoma/pathology , Female , Frameshift Mutation , Genetic Markers , Humans , Male , Middle Aged , Polymerase Chain Reaction , Stomach Neoplasms/pathology
9.
Pathol Res Pract ; 195(11): 747-52, 1999.
Article in English | MEDLINE | ID: mdl-10605694

ABSTRACT

The expression of p53, p16 and RB proteins and their clinicopathologic correlation were investigated in 15 cases of primary gastric adenosquamous carcinoma and 2 cases of squamous cell carcinoma of the stomach. The male to female ratio of the patients was 13:4 and the average age was 55.7 years. None of the cases was early gastric carcinoma, and none of the adenocarcinoma components were of the diffuse or signet ring cell types. Fourteen cases showed metastasis to regional lymph nodes and/or other organs at the time of surgery. The adenocarcinoma component was metastasized to lymph nodes in 12 cases, and both adenocarcinoma and squamous cell carcinoma components were metastasized in three cases. The altered expression of p53 correlated with the advanced stage, but did not correlate with the depth of invasion, lymph node metastasis or recurrence. The altered expression of p16 and RB proteins did not correlate with any of the above clinico-pathologic factors. Both the adenocarcinoma and squamous cell carcinoma components revealed an inverse correlation between the expression pattern of p16 and RB proteins (p < 0.05). This suggests that the two proteins share a role in the carcinogenesis of these tumors. The expression pattern of p53 proteins in the adenocarcinoma and squamous cell carcinoma components was exactly the same in all of the cases. The expression patterns of p16 and RB protein were also identical in most of the cases. The expression patterns of all three proteins in the metastatic lesions were also identical to those in the primary lesions. The fact that the alteration of the three tumor suppressor gene products shares the same pattern suggests that squamous and adenocarcinoma components in the stomach originate from the same or a genetically related clone.


Subject(s)
Carcinoma, Adenosquamous/metabolism , Carcinoma, Squamous Cell/metabolism , Cyclin-Dependent Kinase Inhibitor p16/metabolism , Retinoblastoma Protein/metabolism , Stomach Neoplasms/metabolism , Tumor Suppressor Protein p53/metabolism , Adult , Aged , Carcinoma, Adenosquamous/chemistry , Carcinoma, Adenosquamous/genetics , Carcinoma, Adenosquamous/secondary , Carcinoma, Squamous Cell/chemistry , Carcinoma, Squamous Cell/genetics , Carcinoma, Squamous Cell/secondary , Cyclin-Dependent Kinase Inhibitor p16/analysis , Cyclin-Dependent Kinase Inhibitor p16/genetics , Female , Genes, Tumor Suppressor , Humans , Immunoenzyme Techniques , Male , Middle Aged , Retinoblastoma Protein/analysis , Retinoblastoma Protein/genetics , Stomach Neoplasms/chemistry , Stomach Neoplasms/genetics , Stomach Neoplasms/pathology , Tumor Suppressor Protein p53/analysis , Tumor Suppressor Protein p53/genetics
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