This article deals exclusively with the hereditary forms of colorectal cancer. Clinical examples of hereditary colorectal cancer syndromes abound; of these, familial adenomatous polyposis and Lynch syndrome are the most common and well known (Figure 1).1 In this review, we use Lynch syndrome as an example for the diagnosis, testing of germ cells for mutations, surveillance and management of hereditary colorectal cancer.
Lynch syndrome is the most common hereditary syndrome that predisposes patients to colorectal cancer. It accounts for 2%–5% of the total burden of colorectal cancer.2 The estimated number of new colorectal cancer cases in Canada in 2008 was 21 500.3 Thus, Lynch syndrome accounted for as many as 1075 cases in Canada in 2008. Each patient with Lynch syndrome may represent a family in which multiple family members can be expected to develop colorectal cancer or an integral extracolonic cancer. Clearly, these families have an important impact on public health policy.
The second most common hereditary colorectal cancer syndrome is familial adenomatous polyposis, which is responsible for less than 1% of all colorectal cancer cases.4 Other identified syndromes that predispose patients to colorectal cancer are even less common (Figure 1). However, we still have much to learn about the basis of “familial” colorectal cancer.
In 1966, our team described 2 large families from the mid-western United States with an apparent excess number of members with colorectal cancer that lacked multiple colonic adenomas.5 This disorder involved a variety of extracolonic cancer sites and was therefore initially referred to as the “cancer family syndrome.” It was subsequently renamed hereditary non-polyposis colorectal cancer syndrome. Since the identification of mismatch repair mutations in this syndrome, it has become known as Lynch syndrome6,7 (Online Mendelian Inheritance in Man database no. 120435).8 The name hereditary nonpolyposis colorectal cancer syndrome is given to disorders that have similar phenotypes but that lack the specific mutations involved in Lynch syndrome (e.g., familial colorectal cancer type X).9,10
Advances in molecular diagnostics in the last 15 years have changed the landscape of Lynch syndrome. It is now quite common to identify a germline mutation in one of the mismatch repair genes. The most common mutations are those in MLH1 and MSH2.4 Microsatellite instability testing and immunohistochemistry are useful tools to determine whether a patient is a candidate for testing for mutations in the mismatch repair genes.4,11
Advances in molecular genetics, particularly in the identification of cancer-causing mutations in germ cells, have made it possible to establish whether patients are at high risk of hereditary cancers. In this review, we discuss some of the distinguishing features of hereditary colorectal cancer syndromes and outline the role that primary care physicians play in the detection of hereditary colorectal cancer syndromes and the care of affected patients.