The Molecular Genetics of Colorectal Cancer

Mutations that contribute to colorectal cancer have received extensive study, and this cancer is an excellent example of how cancer often arises through the accumulation of successive genetic defects.

Colorectal cancers arise in the cells lining the colon and rectum. More than 135,000 new cases of colorectal cancer are diagnosed in the United States each year, where this cancer is responsible for more than 56,000 deaths annually. If detected early, colorectal cancer can be treated successfully; consequently, there has been much interest in identifying the molecular events responsible for the initial stages of colo-rectal cancer.

Colorectal cancer is thought to originate as benign tumors called adenomatous polyps. Initially, these polyps are microscopic, but in time they enlarge, and the cells of the polyp acquire the abnormal characteristics of cancer cells. In the later stages of the disease, the tumor may invade the mus cle layer surrounding the gut and metastasize. The progression of the disease is slow; from 10 to 35 years may be required for a benign tumor to develop into a malignant tumor.

Most cases of colorectal cancer are sporadic, developing in people with no family history of the disease, but a few families display a clear genetic predisposition to this disease. In one form of hereditary colon cancer, known as familial adenoma-tous polyposis coli, hundreds or thousands of polyps develop in the colon and rectum; if these polyps are not removed, one or more almost invariably becomes malignant.

Because polyps and tumors of the colon and rectum can be easily observed and removed with a colonoscope (a fiber optic instrument that is used to view the interior of the rectum and colon), much is known about the progression of colorectal cancer, and some of the genes responsible for its clonal evolution have been identified. About 75% of colorectal cancers have mutations in tumor-suppressor gene p53, and many also have a mutation in the ras proto-oncogene. Families with adenomatous polyposis coli carry a defect in a gene called APC, and mutations in APC are found in the cells of tumors that arise sporadically (in persons without a family history). Additional genes that are frequently mutated in colorectal cancer include the onco-genes myc and neu and the tumor-suppressor gene HNPCC.

Mutations in these genes are responsible for the different steps of colorectal cancer progression. One of the earliest steps is a mutation that inactivates the APC gene, which increases the rate of cell division, leading to polyp formation (I Figure 21.25). A person with familial adenomatous polyposis coli inherits one defective copy of the APC gene, and defects in this gene are associated with the numerous polyps that appear in those who have this disorder. Mutations in APC are also found in the polyps that develop in people who do not have adenomatous polyposis coli.

Mutations of the ras oncogene usually occur later, in larger polyps comprising cells that have acquired some genetic mutations. The protein produced by the normal ras proto-oncogene sits inside the cell membrane. From there it relays signals from growth factors that stimulate cell division. When ras is mutated, the protein that it encodes continually relays a stimulatory signal for cell division, even when growth factor is absent.

Mutations in p53 and other genes appear still later in tumor progression; these mutations are rare in polyps but common in malignant cells. Because p53 prevents the replication of cells with genetic damage and controls proper chromosome segregation, mutations in p53 may allow a cell to rapidly acquire further gene and chromosome mutations, which then contribute to further proliferation and invasion into surrounding tissues.

The sequence of steps just outlined is not the only route to colorectal cancer, and the mutations need not occur in the order presented here, but this sequence is a common pathway by which colon and rectal cells become cancerous.

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