Sequence of molecular genetic events in colorectal tumorigenesis

Intensive screening for genetic alteration in colorectal cancer Bed to the identification of two types of colorectal tumours that are distinct by thei r carcinogenesis processes. The first group, named LOH (for loss of heteroz ygosity)-positive, is characterized by hyperploidy and allelic losses invol ving preferentially chromosome 18q and chromosome 17p. More than two-thirds of colorectal cancers belong to this group. The second group, called multi ple microsatellite loci (MSI)-positive cancers, is characterized by genetic instability at microsatellite loci. Although colorectal cancer cells are c haracterized by specific microsatellite alterations, the same four differen t signalling pathways, WNT/Wingless pathway, K-ras pathway, transforming gr owth factor (TGF)beta pathway and p53 pathway, could be implicated in tumou r progression. The WNT/Wingless pathway could be altered in two different w ays according to whether the cancer cells belong to the group of LOH-positi ve or MSI-positive rumours, LOH-positive rumours activate the WNT/Wingless signalling pathway through an adenomatous polyposis coli (APC) mutation, wh ereas the MSI-positive tumours activate this pathway through a beta-catenin stabilizing mutation. beta-Catenin and APC mutations were observed as earl y as the adenomatous stage of colorectal neoplasia, In TGF beta pathways LO H-positive tumours inactivated SMAD2 (similar to mother against decapentapl egic drosophilia) or SMAD4, whereas in MSI-positive rumours the TGF beta ty pe II receptor is frequently deleted. Alteration of these genes correlated closely with the progression of the adenoma to cancer. In the p53 pathway L OH-positive rumours showed frequent p53 mutation, whereas MSI-positive tumo urs demonstrated BAX (BCL-2-associated X protein)-inactivating mutation, Th ese alterations contribute to the adenoma-carcinoma transition. (C) 1999 Li ppincott Williams & Wilkins.