The Genomics of Colorectal Cancer: State of the Art

The concept of the adenoma-carcinoma sequence, as first espoused by Morson et al. whereby the development of colorectal cancer is dependent on a stepwise progression from adenomatous polyp to carcinoma is well documented. Initial studies of the genetics of inherited colorectal cancer susceptibility concentrated on the inherited colorectal cancer syndromes, such as Familial Adenomatous Polyposis (FAP) and Lynch Syndrome (also known as HNPCC). These syndromes, whilst easily characterisable, have a well understood sequence of genetic mutations that predispose the sufferer to developing colorectal cancer, initiated for example in FAP by the loss of the second, normal allelle of the tumour supressor APC gene. Later research has identified other inherited variants such as MUTYH (MYH) polyposis and Hyperplastic Polyposis Syndrome. Recent research has concentrated on the pathways by which colorectal adenomatous polyps not due to one of these known inherited susceptibilities undergo malignant transformation, and determination of the types of polyps most likely to do so. Also, why do individuals in certain families have a predisposition to colorectal cancer. In this article, we will discuss briefly the current state of knowledge of the genomics of the classical inherited colorectal cancer syndromes. We will also discuss in detail the genetic changes in polyps that undergo malignant transformation as well as current knowledge with regards to the epigenomic changes found in colorectal polyps.