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The majority of HNPCC cases are 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. MLH1 and MSH2 are the genes most commonly implicated. Mutations in any one of these genes confers an increased lifetime risk to develop colorectal cancer and, in females, an increased risk to develop ovarian (12%) and endometrial (up to 60%) cancer. 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.
With 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.
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