Mutations in DNA Mismatch Repair Genes. Ann Intern Med. 2003;138:I-53. doi: 10.7326/0003-4819-138-7-200304010-00005
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Published: Ann Intern Med. 2003;138(7):I-53.
Cancer is fundamentally a genetic disorder. A defect, or mutation, in a specific gene can increase cancer risk. Before most mutations become a problem, the cell's built-in repair system usually fixes them in a fashion similar to a computer spell checker. The DNA mismatch repair system recognizes one type of mutation and corrects it by substituting the right chemical structures in the gene. However, when gene mutations occur in the genes for the repair system itself, it may not be able to do its job.
Mutated genes in the DNA mismatch repair system may cause a disorder called hereditary nonpolyposis colorectal cancer (HNPCC), or Lynch, syndrome. People with HNPCC have an increased risk for specific types of cancer, and their risk for colon cancer over their lifetime is very high (80%).
To provide physicians with information on the connection between molecular genetics and clinical care and on how to diagnose, detect, and manage the HNPCC syndrome, including guidelines for genetic testing.
They described normal DNA replication, the process that occurs when a cell divides and copies its genetic information into new cells; explained the mechanisms for repair of gene mutations that may occur during DNA replication; and defined the basis for diagnosing HNPCC.
They showed the consequences of mutations in key genes involved in DNA mismatch repair. When these mutations occur, the DNA mismatch repair system cannot do its job and gene mutations accumulate uncorrected. One type of mutation, called DNA microsatellite instability (MSI), can lead to cancer when it occurs in genes that regulate cell growth. An individual with mutations in key DNA mismatch repair genes develops tumors that have a high level of MSI.
Families displaying only colorectal cancer are classified as HNPCC type I, while HNPCC type II families may also develop extracolonic cancer, usually in the uterus, stomach, ovary, kidney, urinary tract, biliary tract, and small intestine. Cancer progression in persons with HNPCC can be rapid. Frequent surveillance, including annual colonoscopy, can reduce cancer incidence and death.
A clear relationship exists between genetics and cancer. A careful family history is a key way for physicians to assess cancer risk and potentially diagnose cancer before symptoms develop. When a physician takes a family history and discovers that one or more persons had multiple diagnoses of young-onset colorectal cancer (before age 50), HNPCC should be considered. Diagnosis may be made by a genetic test wherein DNA from a blood sample is studied for altered genes in the DNA mismatch repair system.
Genetic testing can be performed in persons with suspected HNPCC to confirm the diagnosis and to assess risk in presymptomatic family members. If HNPCC is diagnosed in a patient through genetic testing, at-risk family members can also be tested. However, HNPCC can still be present even if results on genetic tests are negative. The HNPCC syndrome is genetically complex, and additional, as-yet-unidentified genes may contribute to it.
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Gastroenterology/Hepatology, Hematology/Oncology, Gastrointestinal Cancer, Colorectal Cancer, Prevention/Screening.
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