Sequence of molecular genetic events in colorectal tumorigenesis.
Intensive screening for genetic alteration in colorectal cancer led to the identification of two types of colorectal tumours that are distinct by their carcinogenesis processes. The first group, named LOH (for loss of heterozygosity)-positive, is characterized by hyperploidy and allelic losses involving preferentially chromosome 18q and chromosome 17p. More than two-thirds of colorectal cancers belong to this group. The second group, called multiple microsatellite loci (MSI)-positive cancers, is characterized by genetic instability at microsatellite loci. Although colorectal cancer cells are characterized by specific microsatellite alterations, the same four different signalling pathways, WNT/Wingless pathway, K-ras pathway, transforming growth factor (TGF)beta pathway and p53 pathway, could be implicated in tumour progression. The WNT/Wingless pathway could be altered in two different ways according to whether the cancer cells belong to the group of LOH-positive or MSI-positive tumours. LOH-positive tumours activate the WNT/Wingless signalling pathway through an adenomatous polyposis coli (APC) mutation, whereas the MSI-positive tumours activate this pathway through a beta-catenin stabilizing mutation. Beta-catenin and APC mutations were observed as early as the adenomatous stage of colorectal neoplasia. In TGFbeta pathways LOH-positive tumours inactivated SMAD2 (similar to mother against decapentaplegic drosophilia) or SMAD4, whereas in MSI-positive tumours the TGFbeta type II receptor is frequently deleted. Alteration of these genes correlated closely with the progression of the adenoma to cancer. In the p53 pathway LOH-positive tumours showed frequent p53 mutation, whereas MSI-positive tumours demonstrated BAX (BCL-2-associated X protein)-inactivating mutation. These alterations contribute to the adenoma-carcinoma transition.
Laurent-Puig
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Laboratoire de Toxicologie Moléculaire, INSERM U490, Paris, France. Pierre.Laurent-Puig@biomedicale.univ-paris5.fr
Blons
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Cugnenc
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D000230:Adenocarcinoma / Q000235:genetics*; D015179:Colorectal Neoplasms / Q000235:genetics*; D005260:Female; D015870:Gene Expression; D017491:Genes, APC / Q000502:physiology; D016147:Genes, Tumor Suppressor / Q000502:physiology*; D016158:Genes, p53 / Q000502:physiology; D011905:Genes, ras / Q000502:physiology*; D020022:Genetic Predisposition to Disease; D006801:Humans; D008297:Male; D008967:Molecular Biology; D009154:Mutation; D012680:Sensitivity and Specificity