Different genetic features associated with colon and rectal carcinogenesis.
OBJECTIVE
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.


METHODS
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.
Frattini
Milo
M
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.
Balestra
Debora
D
Suardi
Simona
S
Oggionni
Maria
M
Alberici
Paola
P
Radice
Paolo
P
Costa
Aurora
A
Daidone
Maria Grazia
MG
Leo
Ermanno
E
Pilotti
Silvana
S
Bertario
Lucio
L
Pierotti
Marco A
MA
D000368:Aged; D014408:Biomarkers, Tumor; D002887:Chromosomes, Human, Pair 18; D003110:Colonic Neoplasms / Q000235:genetics*; D003598:Cytoskeletal Proteins / Q000378:metabolism; D004252:DNA Mutational Analysis; D005091:Exons; D005260:Female; D017491:Genes, APC; D016158:Genes, p53; D011905:Genes, ras / Q000235:genetics; D006801:Humans; D007150:Immunohistochemistry; D019656:Loss of Heterozygosity; D008297:Male; D018895:Microsatellite Repeats; D008875:Middle Aged; D009154:Mutation; D012004:Rectal Neoplasms / Q000235:genetics*; D015534:Trans-Activators / Q000378:metabolism; D051176:beta Catenin
D014408:Biomarkers, Tumor; C495270:CTNNB1 protein, human; D003598:Cytoskeletal Proteins; D015534:Trans-Activators; D051176:beta Catenin