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.
The Authors point out the basis for a better characterisation of colo-rectal cancer and precursory lesions. In fact the etiology of familial adenomatous polyposis (FAP), aberrant crypt foci (ACF), ...hereditary non polyposis colon cancer syndrome (HNPCC) seems to be correlated to molecular pathology. Therefore the Authors review colo-rectal cancer natural history which frequently appears to be not related to clinical evolution.
In order to detect loss of heterozygosity (LOH) at APC and MCC genetic loci in gastric carcinoma, the authors established a micro-wax-mediated hot start PCR technique. This method allowed a specific ...gene amplification, and it was useful especially in the amplification of formalin-fixed or stained tissues. In 44 cases of gastric cancer, 29 cases were informative of the APC locus. LOH was found in 8 cases (27.6%): 2 cases in 2 moderately well-differentiated cancer, 2 cases in 13 differentiated cancer, and 4 cases in poorly-differentiated cancer. One of the 3 cases of gastric cancer at early stage also showed LOH. LOH at MCC locus was detected in only 2 of the 25 (8.0%) gastric cancer patients informative. These data suggest that abnormality of APC gene plays a role in the tumorigenesis of gastric cancer and the change may occur at the early stage of tumor development.
About 15% of patients with colorectal cancer have a positive family history: 5% have hereditary colorectal cancer (hereditary non-polyposis colorectal carcinoma (HNPCC), familial adenomatous ...polyposis (FAP) or some other hereditary syndrome), while in 10% no clear hereditary pattern can be recognized ('familial colorectal cancer'). In sporadic and in familial intestinal cancer, a demonstrable hereditary predisposition may undoubtedly exist. HNPCC is often characterized by microsatellite instability, i.e. an increased number of short DNA sequences in the DNA indicating a disorder in DNA repair and a mutation in a DNA 'mismatch repair' (MMR) gene. Indicative of hereditary bowel cancer on the basis of such an MMR gene mutation are: (a) presence of bowel cancer in > or = 3 relatives, (b) early age at the time of the diagnosis of 'bowel cancer', (c) multiple primary bowel tumours, (d) uterine cancer in the family and (e) bowel and uterine cancer in a woman. Recent data demand a new subdivision of hereditary bowel cancer, based upon both the clinical picture and the results of DNA-tests. The genetic alterations in colonic adenomas and carcinomas are known to a large extent. In future these insights may be important in clinical practice, such as a more individual determination of the patient's prognosis and accordingly, of the treatment and follow-up.
One hundred and fifty colorectal adenomas were investigated in order to detect the presence of K-ras gene mutation. The adenomas were classified according to the severity of the histological lesion ...(mild, moderate, or severe dysplasia and carcinomatous transformation) and to the degree of aneuploidy. K-ras mutation was found in 30.8% of cases, mostly consisting of a point mutation of codon 12. K-ras mutation was more frequently found in adenomas > 1 cm and in the villous type. No correlation was otherwise demonstrable with the ploidy pattern of the lesion.
Very frequent loss of heterozygosity (LOH) on chromosome 3p has been found in human renal cell carcinoma (RCC). In the present study, we examined LOH at the retinoblastoma (RB), mutated in colorectal ...cancer (MCC) and adenomatous polyposis coli (APC) tumour suppressor genes loci, and mutations of the H-, K-, and N-ras oncogenes. We performed these studies using the polymerase chain reaction (PCR) method followed by restriction fragment length polymorphism (RFLP) and single-strand conformation polymorphism (SSCP) analyses. LOH was detected in 2 of 11 (18.2%), and 2 of 14 (14.3%) informative cases at the MCC and APC loci, respectively, and in none of 15 informative cases at the RB locus in 25 RCCs. LOH at the MCC was accompanied by LOH at the APC locus in two RCCs. No mutation was detected in H-, K-, and N-ras genes in 39 RCCs. Thus, alterations of the known tumour suppressor genes and the ras oncogenes were infrequent events in RCC. The results suggest that the genetic pathway in the genesis of RCC differs considerably from that of other common human carcinomas.
There is substantial evidence to suggest that inherited predisposition is an important factor in the incidence of colorectal adenomas and carcinomas. The hereditary colorectal cancer syndromes which ...have been most fully characterised are familial adenomatous polyposis (FAP) and hereditary nonpolyposis colorectal cancer (HNPCC). FAP is a dominantly inherited syndrome that results in the development of numerous colorectal adenomatous polyps during adolescence, some of which eventually become malignant at an early age. HNPCC is a clinically distinct non-polyposis syndrome which is dominantly inherited and predisposes to colorectal cancer at an early age without the numerous polyps seen in FAP. In addition, a poorly defined category of non-FAP germline susceptibility to colorectal cancer probably makes up the bulk of the genetic input into the incidence of the disease. HNPCC accounts for around 5% of all cases of colorectal cancer, and 39% of all colorectal cancer patients below the age of 50.
Colorectal carcinogenesis is a multistep process that is accompanied by accumulation of changes in proto-oncogenes and tumor-suppressor genes. APC/MCC, RAS, DCC, p53 mutations and/or allelic losses, ...hyperexpression of c-MYC and RB genes, as well as other genomic alterations appear at characteristic stages of tumor development and are observed in most neoplasms. However, consideration of each of these abnormalities leaves many unanswered questions. The striking data on recurrent amplification of the RB tumor-suppressor gene as well as suppressive activities of protein kinase C and activated RAS genes, at least in some colon carcinoma cell lines, suggest the unusual effects of some signalling pathways in colonic epithelial cells. The results obtained to date indicate that distinct sets of genetic changes may underlie the development of colorectal tumors.
PDF
