Medline ® Abstract for Reference 34
of 'Molecular genetics of colorectal cancer'
Different genetic features associated with colon and rectal carcinogenesis.
Frattini M, Balestra D, Suardi S, Oggionni M, Alberici P, Radice P, Costa A, Daidone MG, Leo E, Pilotti S, Bertario L, Pierotti MA
Clin Cancer Res. 2004;10(12 Pt 1):4015.
PURPOSE: The issue of whether colon and rectal cancer should be considered as a single entity or two distinct entities is still debated, and there is a need to improve studies addressing the heterogeneity of the pathogenetic pathway leading to sporadic colorectal cancers (SCRCs) as well as to identify biological and/or molecular differences between colon and rectal cancers.
EXPERIMENTAL DESIGN: Specimens of SCRCs were analyzed for somatic mutations in APC, K-ras, and TP53 genes and loss-of-heterozygosity of chromosome 18.
RESULTS: Eleven SCRCs showed microsatellite instability. APC mutation frequency was significantly lower in microsatellite instability (MIN+) than in MIN- SCRCs. All MIN- SCRCs showed beta-catenin overexpression. A combined analysis of the biomarkers revealed two pathways mainly represented by MIN- SCRCs and differently followed on the basis of tumor location, APC-K-ras-TP53-Ch18q and APC-TP53-Ch18q.
CONCLUSIONS: The APC-beta-catenin pathway is inactivated in MIN- SCRCs and represents the first hit of SCRC development. Two preferential pathways followed by SCRCs occur, one K-ras dependent, in agreement with the Fearon and Vogelstein model, and the other K-ras independent. Significant differences between colon and rectal tumors occur in our series of MIN- SCRCs. The different pathways observed and their distribution can be summarized as follows: (a) K-ras mutations were more commonly detected in colon than in rectum; (b) the number of mutations detected was significantly higher in colon than in rectal tumors; and (c) a mutational pattern restricted to the APC gene was more common in rectal than in colon tumors. This molecular characterization can be translated into a clinical setting to improve diagnosis and to direct a rationale pharmacological treatment.
Department of Experimental Oncology, Istituto Nazionale per lo Studio e la Cura dei Tumori, and Federazione Italiana Ricerca Cancro, Institute of Molecular Oncology, Milan, Italy.