Genetics of colorectal cancer

Approximately 6% of colorectal cancers can be attributed to recognizable heritable germline mutations. Familial adenomatous polyposis is an autosomal dominant syndrome classically presenting with hundreds to thousands of adenomatous colorectal polyps that are caused by mutations in the APC gene. Adenomas typically develop in the midteens in these patients, and colorectal cancer is a virtual certainty if this condition is untreated. A low-penetrance susceptibility allele that is common in Jews from Eastern Europe, APC I1307K, confers a two-fold increased risk of colorectal cancer without the full expression of familial adenomatous polyposis. Biallelic mutations in the MYH gene are associated with an attenuated familial adenomatous polyposis phenotype. Lynch syndrome (hereditary nonpolyposis colorectal cancer) is an autosomal dominant disorder characterized by early onset of colorectal cancer with microsatellite instability. Mutations in mismatch repair genes lead to a lifetime colon cancer risk of 85% in these patients; carcinomas of the endometrium, ovary, and other organs also occur with increased frequency. Although adenomas are not characteristic of the hamartomatous polyp syndromes such as juvenile polyposis and Peutz-Jeghers syndrome, individuals with these diseases have a markedly increased risk of colorectal cancer relative to the general population. In this review, we will describe the phenotypes, genotypes, diagnosis, and management of hereditary colon cancer syndromes.