Hereditary nonpolyposis colon carcinoma (HNPCC) syndrome dramatically illustrates the role of DNA repair genes in predisposition to cancer. This disorder, characterized by familial carcinomas of the colon affecting predominantly the cecum and proximal colon (Chapter 14), results from defects in genes involved in DNA mismatch repair. When a strand of DNA is being repaired, the products of mismatch repair genes act as “spell checkers.” For example, if there is an erroneous pairing of G with T, rather than the normal A with T, the mismatch repair genes correct the defect. Without these “proofreaders,” errors accumulate at an increased rate. Mutations in at least four mismatch repair genes have been found to underlie HNPCC (Chapter 15). Each affected individual inherits one defective copy of one of several DNA mismatch repair genes and acquires the second “hit” in colonic epithelial cells. Thus, DNA repair genes affect cell growth only indirectly—by allowing mutations in other genes during the process of normal cell division. A characteristic finding in the genome of patients with mismatch repair defects is microsatellite instability (MSI). Microsatellites are tandem repeats of one to six nucleotides found throughout the genome (Chapter 1). In normal people, the length of these microsatellites remains constant. By contrast, in patients with HNPCC, these satellites are unstable and increase or decrease in length. Although HNPCC accounts for only 2% to 4% of all colonic cancers, MSI can be detected in about 15% of sporadic cancers due to acquired mutations that disrupt the function of mismatch repair genes.
Xeroderma pigmentosum is an autosomal recessive disorder caused by a defect in DNA repair that is associated with a greatly increased risk for cancers arising in sun-exposed skin. Ultraviolet (UV) rays in sunlight cause cross-linking of pyrimidine residues, preventing normal DNA replication. Such DNA damage is repaired by the nucleotide excision repair system. Several proteins are involved in nucleotide excision repair, and the inherited loss of any one of these can give rise to xeroderma pigmentosum.
A group of autosomal recessive disorders comprising Bloom syndrome, ataxia-telangiectasia, and Fanconi anemia is characterized by hypersensitivity to DNA-damaging agents, such as ionizing radiation (in Bloom syndrome and ataxia-telangiectasia), or to DNA cross-linking agents, such as nitrogen mustard (in Fanconi anemia). Their phenotype is complex and includes, in addition to predisposition to cancer, features such as neural symptoms (in ataxiatelangiectasia), anemia (in Fanconi anemia), and developmental defects (in Bloom syndrome). The gene mutated in ataxia-telangiectasia is ATM, which encodes a protein kinase that is important in “sensing” DNA damage caused by ionizing radiation and then directing p53 to initiate the DNA damage response, as described earlier.