Genetics and Cancer - Hereditary Nonpolyposis Colon Cancer (HNPCC)
A woman is at increased risk for ovarian cancer if she has Lynch syndrome, also called hereditary nonpolyposis colon cancer (HNPCC). Lynch syndrome is an autosomal dominant genetic cancer syndrome. Having this syndrome means a woman has a 4 to 12 percent risk for ovarian cancer by about 42 years of age. About 30 percent of women diagnosed with ovarian cancer are diagnosed before age 40.
A clinical diagnosis of Lynch syndrome is made when the following characteristics are present in a family:
- Three or more relatives with HNPCC-related cancer (colorectal, endometrial, ovarian, small bowel, stomach, liver, brain, upper respiratory tract, skin, prostate, gallbladder ducts, ureter, or renal pelvis)
- Cancer affecting at least two successive generations
- One person with cancer is a first-degree relative (parent, child, sibling) of the other two
- At least one case of HNPCC-associated diagnosed under age 50
- A diagnosis of familial adenomatous polyposis has been ruled out
However, some families with mutations in HNPCC-related genes may be tested even though they may not have all of the above characteristics. Genetic testing for Lynch syndrome should include the steps of molecular analysis for germline mutations, tumor testing for microsatellite instability, and tissue testing for immunohistochemistry.
The majority of Lynch syndrome cases are caused by mutations in one of several mismatch-repair genes: MSH2 and MSH6 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 and account for approximately 90 percent of cases.
These mismatch-repair genes help correct "spelling errors" in DNA that happen during the cell division process. When these genes are altered, or mutated, then the "spelling errors" in the DNA cannot be repaired.
These errors in the DNA can lead to uncontrolled cell growth, which causes cancer. In Lynch syndrome, the germline mutation may be inherited from either the mother or the father and is present in all cells of the body. Whether a person who is born with a germline mutation will develop cancer, when they may develop cancer, and where the cancer(s) will appear depends on 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, then ovarian cancer may develop. The process of tumor development actually requires mutations in multiple growth control genes. 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 people who have inherited a germline mismatch-repair gene mutation never develop cancer because they never receive that second mutation 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, even when the mutation is present. People with a mutation, regardless of whether they develop cancer, have a 50/50 chance (autosomal dominant) to pass the mutation on to each of their children.
It is also important to remember that the mismatch-repair genes responsible for Lynch syndrome are not located on the sex chromosomes. Therefore, mutations can be inherited from the mother's or the father's side of the family.
Click here to view the
Online Resources of Cancer Center