Molecular pathology of colorectal cancer

Abstract

Colorectal cancer is one of the most intensively studied cancer types, partly because of its high prevalence but also because of the existence of precursor lesions, known as adenomas, which can be detected endoscopically and removed. Theoretically, removal of these adenomas would prevent most cases of colorectal cancer from developing. Characteristic morphological steps in the evolution of these precursor lesions have been elucidated at a molecular level and the adenoma-carcinoma sequence, as this has become known, is one of the classical examples of stepwise progression of cancer. Gaining this knowledge has been facilitated by the occurrence of a variety of forms of familial intestinal cancer, the molecular genetic background of which has been largely clarified. Apart from early detection of familial forms of colorectal cancer and its use in genetic counseling, until recently this knowledge has had little impact on the clinical management of colorectal cancer. Classical clinicopathological parameters remain the essential parameters determining how a colorectal patient will be treated. This has dramatically changed in the last five years. With drugs specifically targeting the EGF receptor having been shown effective in colorectal cancer, mechanisms responsible for resistance have been explored. The finding that KRAS-mutated cancers do not respond to anti-EGFR treatment has had a profound impact on clinical management and on molecular diagnostics of colorectal cancer. With new targeted drugs in the pipeline it is highly likely that companion diagnostics will go through a period of explosive development. In this chapter we will discuss the biology of intestinal mucosa and its disturbance in cancer. We will review cancer family syndromes and the impact of understanding these on a molecular level has had on our understanding of colorectal cancer. Finally we will review how molecular diagnostics now contribute to the clinical management of colorectal cancer and what can be expected in this field in the near future.