| Abstract |
Cancer nowadays is considered the result of additive defects on genomic DNA. Carcinogenesis is a multistage process in which oncogene activation, tumor suppressor gene and mismatch repair gene inactivation, along with other DNA defects in various order and participation, lead to clonal cell expansion, with survival advantages and capability of intruding and metastasizing. Ras oncogene family (K-, H- and N-ras) is often activated in various cancer and precancerous conditions. Different rates of ras genes activation have been found in colorectal cancer in various studies. Colorectal cancer is the fourth most common type of human cancer. Its slow evolution and the relatively easier detection of precancerous lesions have prolonged survival nowadays. Colorectal adenomas are the commonest precancerous lesions. Of interest in colorectal cancer and adenomas is the variable incidence in populations of different geographic areas, and that emigrants tend to acquire the rate of colorectal cancer of the host region. The aim of the present study was the detection of activation of the three ras genes, due to codon 12 point mutations, in colorectal adenomas and adenocarcinomas in Greek population and the relation between these and clinical or pathologic features of the tumors. Polymerase chain reaction (PCR) was used for the amplification of the relevant regions and restriction fragment length polymorphism (RFLP) was used for the detection of codon 12 point mutations. Seventy-eight adenomas from 73 patients and 76 adenocarcinomas from 75 patients were studied. There was no H-ras mutation found in adenomas or adenocarcinomas. This indicates that H-ras is not implicated in colorectal carcinogenesis through activation of the proto-oncogene. One mutation in N-ras was found in adenomas (1/78) and adenocarcinomas (1/76), therefore it seems that qualitative changes of this gene, do not confer to tumorigenesis in large intestine. K-ras mutations were found in 42.3% (33/78) of adenomas and 36.8% (28/76) of adenocarcinomas. Regarding adenomas, gender, location, previous cancer history or stalk existence do not seem to correlate with mutation rate. K-ras mutations were more often (p=0.018) in patients above 64 years old, a cutting point which was the mean age of the patient group. In the 5 patients with synchronous adenomas, when one adenoma bared a mutation, the other had mutation too. Two out of 5 synchronous adenomas carried mutations. Whenever though, there was a history of previous polypectomy, mutations tended to be less frequent (p=0.121), compared with patients with negative history. Adenomas with high grade of dysplasia had mutations more often (p=0.197), compared with adenomas of moderate or mild dysplasia. Adenomas with foci of in situ Ca carried mutations more frequently (p=0.203). There was no correlation found between histologic type or size of adenomas and K-ras mutations, although mixed adenomas larger than 2 cm carried mutations more often (p=0.043), than mixed smaller adenomas. Regarding adenocarcinomas patient?s gender, location of tumor, or Dukes? stage were not correlated with the incidence of K-ras mutations. A trend for mutations to be more often in patients younger than 50 years old was observed (p=0.067). Under this age colorectal cancer is considered to have a hereditary background. In the patient with two synchronous colorectal adenocarcinomas, mutations were found in both locations. High grade of differentiation adenocarcinomas had statistically significant (p=0.001) more mutations, than the intermediate or low grade ones. Higher mutation rate was found in mucous secreting adenocarcinomas (p=0.22), and in those that did not have foci of necrosis in the tumor mass (p=0.14). Statistically significant more frequent mutations were found in adenocarcinomas with elements developing from adenoma (p=0.016), and in female who had the tumor located in the rest of the colon (p=0.013), in comparison with rectosigmoid location. From the results of the present study it seems, that H- and N-ras codon 12 point mutations are not implicated in the evolution of sporadic forms of colon cancer. Regarding K-ras mutations, the relatively lower incidence found, compared with other studies, might confer to the lower incidence of colorectal cancer seen in Greek population. Although K-ras mutations are implicated in the development of colorectal cancer, carcinogenesis in the large intestine might follow different, ras-independent pathways. However, in cases of ras-dependent process, our results confer in favor of the development of less aggressive neoplasms.
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Συγκριτικός έλεγχος της ενεργοποίησης των ογκογονιδiων ras σε καλοήθη και κακοήθη νεοπλάσματα του παχέος εντέρου
