The genetic etiology of familial and nonfamilial colorectal cancer.

Colorectal cancer (CRC) is the third most frequently diagnosed cancer in the US and the second leading cause of cancer death. CRCs arise from a multistep carcinogenic process, beginning with early changes from normal to hyperproliferative epithelium, then to the development of adenomas, which in turn are believed to be precursors of carcinomas. These histological changes are associated with the accumulation of genetic and epigenetic changes involving the activation of oncogenes and the inactivation of tumor suppressor genes. Approximately two thirds of new cases of CRC appear to be sporadic (i.e., occur without a family history of the disease), and the necessary genetic changes seem to arise de novo, fueled by etiologic agents that can include age, environmental exposures, and lifestyle factors. Nearly one third of cases, however, tend to cluster in families, so that first-degree relatives of patients with newly diagnosed adenomas or invasive CRCs are at increased risk. While many of these familial clusters may be linked to shared behaviors or environmental exposures among family members, some are associated with germline mutations in specific genes. Although specific genetic mutations have been identified for a wide variety of syndromes that may involve CRC, screening is normally directed at the most common of these: hereditary nonpolyposis CRC (HNPCC), also known as Lynch syndrome, and familial adenomatous polyposis (FAP). Lynch syndrome is the most common hereditary cancer syndrome predisposing to CRC, accounting for approximately 3% of all cases. It is associated with mutations in four DNA-mismatch repair (MMR) genes: MSH2, MLH1, MSH6, and PMS2. Individuals with a germline mutation in any of these genes have a significant lifetime risk of developing CRC (70% for men, 40% for women), as well as a heightened risk for the development of cancers at other sites, including the endometrium, ovary, stomach, small bowel, urinary tract, and pancreas. FAP, about one tenth as common as Lynch syndrome, is associated with mutations in the APC gene, which is classified as a tumor suppressor gene. Individuals with FAP may have hundreds of adenomas, making this syndrome relatively straightforward to detect. Because so many adenomas develop at an early age, classic FAP carries a lifetime risk of nearly 100% for the development of CRC. Additional hereditary CRC syndromes that are not routinely tested for include Peutz-Jeghers syndrome, familial juvenile polyposis, Cowden's disease, Bannayan-Ruvalcaba-Riley syndrome, and Li-Fraumeni syndrome. For both sporadic and familial CRC, a key early change is the development of genetic and epigenetic instability, which increases the rate at which further changes can be accumulated. At least three patterns of instability can contribute to the development of CRC; typically, one type will predominate in a specific cancer. One common pattern, prominent in at least 50% of CRCs, is chromosome instability (CIN), which can result in genetic deletions, duplications, and rearrangements. CRCs with CIN are characterized by aneuploid tumor cells. A second pattern is microsatellite instability (MSI), which occurs in about 15% of CRCs (Figure ​(Figure11). Microsatellites are simple repeat sequences 1 to 6 base pairs in length that occur thousands of times across the genome. MSI occurs through the inactivation of the DNA mismatch repair (MMR) system, resulting in sequences that accumulate errors and become abnormally long or short. In some instances, this creates a frameshift mutation in a gene, such as a tumor suppressor gene. Unlike CIN, most CRCs with MSI are diploid or near diploid. More than 90% of the CRCs attributable to Lynch syndrome are associated with MSI. Figure 1 Two molecular pathways to the development of colorectal cancer with microsatellite instability. From Boland CR, Goel A. Microsatellite instability in colorectal cancer. Gastroenterology 2010;138(6):2073–2087.e3. Reprinted with permission from ... The third pattern seen in CRC is an epigenetic change that involves the methylation of promoters of human genes. This can lead to the silencing of certain tumor suppressor genes in CRC. About half of the promoters of human genes are embedded in CpG islands, so this phenotype in tumor DNA is called the CpG island methylator phenotype (CIMP). Overlap between MSI and CIMP occurs in about 12% of CRCs when the promoter of the MMR gene MLH1 is methylated (and inactivated), leading to MSI.