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Colorectal cancer (CRC) exhibits a strong familial risk with first-degree relatives of cases having a two to three times greater risk of developing CRC than the general population. An estimated 35% of CRC cases are due to genetic factors. Highly penetrant predisposing genes have been identified for several inherited CRC syndromes (e.g., FAP, Lynch syndrome, and juvenile polyposis) through genetic linkage studies. However, despite these considerable successes, mutations in these rare syndromes explain less than 6% of CRCs and only a small fraction of familial risk. While two recently described syndromes, MUTYH-associated polyposis, with its pattern of recessive inheritance, and familial CRC type X, account for additional genetic burden, they still account for only a small fraction of CRC risk. In the last few years, considerable effort has been directed toward the identification of common, low-penetrance mutations through the promising approach of genome-wide association studies (GWAS). With respect to CRC, 15 novel disease loci have been identified through GWAS including several genes involved in the TGFβ signaling pathway. The familial and population risks explained by these loci remain small, but it is expected that additional novel susceptibility markers will be identified as larger ongoing and pooled GWAS are completed. While the role of the majority of susceptibility genes identified through linkage studies and GWAS in energy balance remains unclear, a pattern is emerging of a possible link given that several TGFβ-related genes have been implicated in energy balance including susceptibility genes identified through linkage analyses or GWAS.

This simple question should be a routine part of every patient history and is particularly important in patients presenting with bowel-related complaints. This chapter will discuss the significance of a family history of colorectal neoplasia, describe the way to obtain a reliable family history, and recommend follow-up of the possible answers.

Predicting the future in medicine is a difficult task, especially in the field of molecular genetics. The rate of progress over the last 8 years has been so great that were it to continue, developments might occur that today are unthinkable. Many of the recent advances have not yet become routine clinical tools, but the next few years will likely see this happen. The effects of future developments and the transfer of current technology from the laboratory to the bedside will have profound effects on all aspects of care of patients with colorectal neoplasia. In this chapter some of the potential effects are discussed.

Because each gene codes for a unique protein with a unique function, change in the way the genes are translated into protein may have important implications for cellular function. Genes may be abnormally activated, as with proto-oncogenes in their transformation to oncogenes, or genes may lose function, as with tumor suppressor genes. Genes may lose function by mutation, by loss of chromosomal material, or by promoter hypermethylation. In addition the expression of a normal gene may vary because of modifying genes or other factors in the cellular environment. Understanding how genes lose function is important in understanding how colorectal neoplasia develops.

Patients and families identified as having a dominantly inherited syndrome of colorectal cancer need education, support, and lifelong management of the clinical aspects of the syndrome. Although many such patients are strongly motivated to research their own condition and make full use of all resources available, they need expert care. Care of such families is a commitment that grows as family connections are unearthed and as new generations expand the numbers of potential patients. Who will be available to answer questions for the family, to help them arrange surveillance appointments, to issue reminders to forgetful relatives, to assist in dealing with insurance companies, to coordinate surgery? These are not functions of any single physician, but they fall under the umbrella of an organization formed specifically to carry them out; a Genetics department, Center or Registry.

The way in which a cell responds to and interacts with its environment is critical for normal organ function and is given a high priority in the metabolic pathways that exist in and around each cell. Signals exchanged between normal cells and their environments control cell growth, migration, differentiation, senescence and death. Cancer cells have escaped these signals and are thus beyond the normal regulation of cell growth. In this chapter the mechanisms governing normal cell growth, migration, differentiation and death are reviewed so that the ways in which cancer cells become different to normal cells can be understood.

The ways in which the structure and function of genes are studied are a mystery to most clinicians. In this chapter the technology behind genetic testing will be explained although the methods will not be described in detail.

“Genetics” is derived from the Greek word “gennan”, meaning, “to produce.” Genetics is the study of genes, and genes are sections of the DNA molecule that code for, or ‘produce’, a specific protein. There are tens of thousands of genes in a molecule of human DNA. All of them code for specific proteins with unique functions, functions that are sometimes evident (e.g. eye color, height) and sometimes not. Normal variations in gene structure and expression between individuals produce differences in protein structure and function that are responsible for the natural diversity of our species. Abnormalities of gene structure (mutations) and expression can change protein function in ways that produce a wide variety of diseases. These are genetic diseases. Colorectal cancer is a genetic disease. A genetic disease can be inherited when a key mutation involved in its pathogenesis is transmitted from parent to child during conception, and some colorectal cancer syndromes arise like this.

There are two main syndromes in which a tendency to develop colorectal cancer is transmitted by dominant inheritance (inheritance that requires the transmission of only one mutated copy of a gene for the disease to become manifest). These syndromes are familial adenomatous polyposis (FAP) and hereditary non-polyposis colorectal cancer (HNPCC). Although they account for

Although colorectal cancer is the third most common malignancy of the internal organs some basic terms used in describing this disease are often misused or poorly understood. The purpose of this chapter is to minimize confusion by defining these terms and explaining them in the context of their underlying genetic changes.

Modern molecular genetic techniques applied to human cancers have shown that cancer is a genetic disease. This is particularly obvious in the development of colorectal cancer because colorectal neoplasia usually follows a predictable developmental sequence and genetic events accompany each step. The histological sequence starts with hyperproliferation of the colorectal mucosa, leading to an aberrant crypt focus (ACF). These are the smallest visible forms of neoplasia. From such an area arises the benign precursor of colorectal cancer, the adenomatous polyp. A small fraction of adenomas progress along a pathway of increasingly severe dysplasia, ultimately becoming invasive (malignant) and then metastasizing. This pathway is followed by both inherited and sporadic colorectal cancers, illustrating the clonal evolution underlying the progression (Figure 6.1).