Pathogenesis of colorectal cancer

Abstract

It is frequently stated that all but a few colorectal cancers arise in adenomatous polyps, in turn initiated by APC mutation. Moderation of this view is now required. The proportion of colorectal cancers that arises in a polypoid adenoma is likely to be around 70% [39,61]. The pre-eminence of the adenoma-carcinoma model has been influenced by two factors: (1) the need to avoid overtreatment of innocent lesions, and (2) the absence of a convincing alternative mechanism. The latter position has changed in recent years. Collectively, the alternative pathways may account for the pathogenesis of up to 30% of colorectal cancers. The alternative pathways are difficult to observe in clinical practice because the precursors may be either inconspicuous or show rapid evolution following the establishment of genetic instability. As a concept, the polyp-cancer sequence is entrenched in both specialized and student texts. This is unfortunate, because progress in prevention and early cancer detection will be delayed by the failure to adopt a critical and nondogmatic approach to the pathogenesis of colorectal cancer. The advent of DNA chip technology will catalyze the development of revised paradigms. Specifically, modern genomics will allow polyps and cancers to be grouped within pathogenic pathways on the basis of shared gene expression profiles. The era of molecular medicine has dawned for colorectal cancer.