During the investigators's studies on the role of somatic mutational activation of the c-K-ras gene in human colo-rectal tumorigenesis, they have found that differences in the molecular nature of mutations occurring in the c-K-ras locus are significantly correlated with differences in the development, stage of progression and time of cancer onset. More specifically, aspartic acid substitutions at codon 13 (ASP13 mutations) of the c-K-ras gene are found predominantly in adenomas and in carcinomas of older patients compared with those containing other c-K-ras mutations or in tumors without ras mutations. The investigators working hypothesis postulates that the structural changes induced in the c-K-ras gene product by the ASP13 mutation confer a weaker oncogenic activity to the protein relative to other activating mutations, especially the aspartic acid mutation at codon 12 (ASP12 mutation). This submicroscopic difference underlies a pleiotropic chain of events resulting in ultimate macroscopic differences that can be as obvious as a delay of 5-10 years in the onset of symptomatic neoplasia. The main goal of this proposal will be to analyze the molecular basis for the late onset of colo-rectal carcinomas with the c-K-ras ASP13 mutation, by testing a number of predictions that the investigators hypothesis postulates. The investigators will carry out a comparative analysis of: 1) the relative extent of oncogenic genetic damage in colo-rectal tumors with and without this mutation; 2) the biological (2a) and biochemical (2b) properties of c-K-ras p21 with the ASP13 versus other mutations in vitro; 3) the relative oncogenic penetrance of c-K-ras genes with this and other mutations in vivo; and 4) the relative accessibility or sensitivity to carcinogens of c-K-ras codon 13 versus codon 12 in vitro (4a) and in vivo (4b). The investigators studies should define the molecular mechanisms underlying the intrinsic differences in the oncogenic potential of the most predominant of all the ras mutations, the ASP12 and ASP13 mutations, and bear directly on the issue of the role in initiation of carcinogenesis of the ras oncogene most commonly found in spontaneous and carcinogen-induced tumors, the c-K-ras.
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