Chromosomal instability pathway

Colorectal cancer (CRC) is the second leading cause of cancer death in the United States, with about 5% of cases associated with inherited mutations linked to colon cancer syndromes. The molecular basis of sporadic and inherited CRC involves two distinct pathways, one of chromosomal instability and one associated with microsateUite mstabifity. The original model of chromosome instability proposed in 1990 to explain the pathogenesis of most sporadic tumors (-85%) has been further characterized to reveal a complex chain of events whereby normal colon fining (mucosa) is transformed... 

Loss of A PC function leads to uncontrolled activation of the Wnt// -catenin pathway and provides a proliferative advantage to the mutated cell (reviews Moon et al., 2002 Fodde, 2003). In addition, chromosomal instability is observed in cells with decreased APC function. The C-terminus of APC encompasses domains responsible for proper attachment of the mitotic spindle to the kinetochore, and it is assumed that loss of this function elicits chromosomal instability. It is remarkable that two central aspects of tumor formation, namely proliferative advantage and chromosomal instability, are observed upon deactivation of the Wnt// -catenin pathway. Malfunction of other components of the Wnt/ -catenin pathway has also been observed in tumors. The scaffold protein axin has been... 

Chromosome 9 alterations are established to be the earliest events in both pathways of URCa development, setting up the stage for genetic instability that in turn leads to accumulation of subsequent genetic events. Among... 

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