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HNPCC is also known as Lynch syndrome, or Cancer Family Syndrome. The majority of HNPCC is caused by mutations in one of several mismatch-repair genes: MSH2, MSH6, and PMS1 on chromosome 2, MLH1 on chromosome 3, MSH3 on chromosome 5, and PMS2 on chromosome 7. MSH2 and MLH1 account for the majority of mutations in HNPCC families. Mutations in any one of these genes confers an increased lifetime risk to develop colorectal cancer, as well as cancers of the endometrium, stomach, small intestine, liver and biliary tract, brain, ovary, ureters, and renal pelvis. Specifically, there is a 70-82% lifetime risk to develop colorectal cancer, a 12% chance to develop ovarian cancer, and up to a 60% chance to develop endometrial cancer.
There are two approaches to performing genetic testing in families with suspected HNPCC. One approach is to proceed directly to mutation analysis of the MSH2, MLH1, and possibly MSH6 genes (testing a blood sample for germline mutations in these mismatch-repair genes). This approach is often taken when a family history clearly meets the criteria reviewed above. The second approach is to first test a tumor tissue sample for a characteristic called "microsatellite instability before considering mutation analysis". In human cells, there are repeated sequences of DNA referred to as "microsatellites." Although the length varies from person to person, each person has microsatellites of a set length. In cells that have mutations in mismatch-repair genes, some of these DNA sequences accumulate errors and become longer or shorter. This phenomenon is known as "microsatellite instability," or MSI.
Ninety percent of colorectal cancers from people with HNPCC exhibit MSI. (This characteristic is present in only 15-20% of sporadic colon cancers.) If a tumor is found to exhibit MSI, then the patient/family may consider germline mutation testing of the mismatch-repair genes (MSH2, MLH1, and MSH6) for which commercial gene tests are available. In research studies, it has been observed that there are some patients with non-classic HNPCC that do not have MSI, but do have a mutation in a mismatch-repair gene such as MSH6. Also, not everyone with HNPCC will have an identifiable mismatch-repair gene mutation.
As mentioned, the genes responsible for HNPCC are mismatch-repair genes, which correct "spelling errors" in DNA that happen during the cell division process. When these genes are altered, or mutated, however, mismatches in the DNA remain. If mismatches accumulate in cell growth control genes, like proto-oncogenes and tumor suppressor genes, this will eventually lead to uncontrolled cell growth and tumor formation. Both copies of a mismatch-repair gene must be altered, or mutated, before a person will develop cancer.
In HNPCC, the first mutation is inherited from either the mother or the father and is therefore present in all cells of the body. This is called a germline mutation. Whether a person who has a germline mutation will develop cancer and where the cancer(s) will develop depends upon where (which cell type) the second mutation occurs. For example, if the second mutation is in the colon, then colon cancer may develop. If it is in the ovary, ovarian cancer may develop.
The process of tumor development actually requires mutations in multiple growth control genes. Loss of both copies of a particular mismatch-repair gene is just the first step in the process. What causes these additional mutations to be acquired is generally unknown. Possible causes include chemical, physical, or biological environmental exposures or chance errors in DNA replication.
Some individuals who have inherited a germline mismatch-repair gene mutation never develop cancer because they never get the second mutation necessary to knock out the function of the gene and start the process of tumor formation. This can make the cancer appear to skip generations in a family, when, in reality, the mutation is present. Persons with a mutation, regardless of whether they develop cancer, however, have a 50/50 chance to pass the mutation on to the next generation.
It is also important to remember that the mismatch-repair genes responsible for HNPCC are not located on the sex chromosomes. Therefore, mutations can be inherited from the mother or the father's side of the family.