Beyond the adenomatous poiyposis coli era: alternative pathways to colorectal cancer

摘要

One of the practical benefits of an evolutionary model for cancer is to identify the earliest stages that could be either eliminated or targeted by specific interventions. Colorectal neoplasia has been viewed as a developmental continuum that begins with the initiation of an adenoma and culminates with the emergence of a subclone with malignant properties. During its progression to cancer, the precursor lesion evolves in a stepwise manner governed by genetic alterations. Progression of a precancerous adenoma may be marked by growth, increasing dysplasia, and development of a villous architecture. The genetic changes underlying this morphogenesis will be preserved within the end-lesion as a permanent record of the evolutionary history. Since any precursor lesion is usually destroyed by the time a colorectal cancer (CRC) presents clinically, the genetic history as recorded in the cancer DNA provides important evidence of the early evolutionary steps. Associated with this linear model are two central beliefs. The first is that mutation of APC explains the initiation of most adenomas. The second is that most, if not all, CRCs arise within a pre-existing adenoma. This chapter will critically examine the role of APC as the initiating step in colorectal neoplasia and will then highlight the importance of lesions other than the classical adenomatous polyp in colorectal tumorigeneis. The biochemistry of APC protein and the Wnt signalling pathway will not be discussed.