The clinicopathological characteristics of esophageal cancer have gradually been clarified using molecular biologic methods developed over the past 20 years. For example, amplification of the c-erb B ...gene is a prognostic factor and predictive of lymph node involvement, while the amplification of the cyclin D1 gene is also a prognostic factor and predictive of distant organ metastasis. Alteration of the p16 gene is also a prognostic factor and predicts lymph node involvement. As telomerase activity is almost a unique phenomenon of cancer cells, highly sensitive detection of esophageal cancer cells in the peripheral blood can be performed. Recently, such new methods as comparative genomic hybridization analysis and cDNA microarray analysis have been used to determine meaningful genetic changes. For therapeutic purposes, although tailor-made therapy has been proposed for several years, the validity of these approaches should be confirmed in a well-designed clinical trial. As molecular targeted therapies, tyrosine kinase inhibitors of epidermal growth factor receptor (EGFR) and monoclonal antibodies against EGFR are being studied in clinical trials in Western countries. A clinical trial of p53 gene therapy against esophageal cancer is also promising.
The enormous progress made in the identification of genes that are involved in colon carcinogenesis has provided the foundation for further understanding the biology of both normal and cancer cells ...and for targeted therapeutic strategies. In one sense, the genes described in this review are only the building blocks of a larger puzzle that constitutes the integrated metabolic function of a cell. The current challenge is to understand the functional role of these genes in normal cellular physiology and make the connections between pathways that knit together integrated cellular homeostasis. A complete understanding of the regulatory pathways, and the synthesis and modifications of the proteins involved, will provide novel targets for therapeutic agents.
We examined 26 gastric carcinomas from British patients for mutations of the APC gene using a single-strand conformation polymorphism (SSCP) and heteroduplex assay in conjunction with the protein ...truncation test (PTT). In addition, we performed loss of heterozygosity (LOH) analysis of the APC and MCC genes. We detected an inactivating somatic mutation in one gastric tumour. LOH of APC was observed in one of 12 informative cases (8%) and of MCC in two of 20 cases (10%). We thus find that alteration of the APC and MCC genes are infrequent in gastric cancers from the British population. Tumour-suppressor genes on other chromosomes must play a more significant role in the development of these tumours.
In familial juvenile polyposis, multiple juvenile polyps occur throughout the colon. The genetic defect has not been characterized. The risk of colon cancer is increased, although the magnitude of ...the increased risk is controversial. The hypothesis of this study was that the genetic defect is within a tumor suppressor gene, possibly one already known to be inactivated in colorectal neoplasia.
Linkage analysis using the short tandem repeat polymorphism D5S346 was performed to determine if juvenile polyposis was linked to either APC (adenomatous polyposis coli) or MCC (mutated in colorectal carcinoma) genes within a single large family.
A family in which eight subjects have been affected by juvenile polyposis over three generations is described. Six affected subjects had colectomies in childhood, but the two who have so far survived beyond 35 years of age have developed adenocarcinoma of the jejunum. Within this family, linkage analysis excluded linkage of the juvenile polyposis trait to either APC or MCC.
In a family with juvenile polyposis with a clear predisposition to malignancy, including carcinoma of the jejunum, APC and MCC were not the defective genes causing the condition.
The adenoma-carcinoma sequence has its molecular basis in several gene mutations of which K-ras and p53 are of paramount importance. The aims of this study were to evaluate whether these genetic ...alterations can be detected in colonic lavage fluid from patients with colorectal adenomas and carcinomas.
In 45 patients with adenomas, 20 patients with colorectal carcinomas and 38 patients with non-neoplastic and noninflammatory diseases of the colon p53 and K-ras mutations were evaluated in colonic lavage fluid employing single-strand confirmation polymorphism analysis and dot-blot hybridization, respectively.
Mutations of the K-ras and the p53 gene were found in 15.6% (p = 0.065) of patients with adenomas, in 25.0 % (p = 0.016) of patients with carcinomas and in 2.6% in the control group.
Genetic alterations in the colonic lavage fluid could be an additional diagnostic tool for the surveillance of patients with colorectal neoplasias.
In order to assess the role of the changes of DCC and APC/MCC genes in the development and progression of gastric cancer, the loss of heterozygosity (LOH) of these genetic loci was investigated in 45 ...surgical specimens of gastric cancer with PCR-RFLP. The rate of LOH was 30.0% (9/30) at APC/MCC gene and 33.3% (15/45) at DCC gene. LOH was found in both intestinal and gastric types of gastric cancer and the rate of LOH of DCC gene was significantly higher in stages III to approximately IV gastric cancer (48.0%) than in stages I to approximately II (15.0%) (P<0.05). LOH of APC/MCC gene could be found in both early and advanced stages of gastric cancer. These findings suggest that changes of DCC and APC/MCC genes are involved in the development and progression of the intestinal and gastric types of gastric cancer.
Recently, two genes in 5q21 involved in colon carcinogenesis, APC and MCC, were identified, and also shown to be associated with the development of esophageal and lung cancers. To determine if these ...genes are also involved in the development of gastric cancer, 79 primary human gastric cancers were examined for loss of heterozygosity of APC or MCC or both. Loss of APC was detected in 20% of 15 informative differentiated cases, but not in 20 informative undifferentiated cases, while loss of MCC occurred in 23.5% of 17 informative undifferentiated cases, but not in 19 informative differentiated cases. These data suggest that loss of heterozygosity of APC/MCC gene is involved in the development of gastric carcinomas, and that distinctly different molecular mechanism(s) may be responsible for the development of differentiated and undifferentiated gastric carcinomas.
To investigate the alterations of APC, MCC and DCC genes in human esophageal carcinoma.
A total of 46 human esophageal cancer specimens were analyzed for the loss of heterozygosity (LOH) at APC, MCC ...and DCC genetic loci by means of polymerase chain reaction and restriction fragment length polymorphism.
The incidence of LOH was 29.0%(9/31) at APC locus, 33.3%(8/24) at MCC locus, and 32.4%(12/37) at DCC locus, respectively. However, there was no statistically significant correlation between LOH at these three loci with such clinical parameters as pathological types, tumor size, invasiveness, and lymph-node metastasis.
These data suggest that LOH at APC, MCC and DCC loci in esophageal carcinoma is, to certain extent, a common genetic alteration which might play a role in esophageal carcinogenesis.
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