Lynch (HNPCC) syndrome

The risk for gynecologic cancer is increased with Lynch syndrome, also known as hereditary nonpolyposis colon cancer (HNPCC), an autosomal dominant cancer genetic syndrome. A clinical diagnosis of Lynch syndrome is made when all of the following characteristics are present in a family:

  • Three or more relatives with colorectal cancer or other HNPCC-related cancer (cancer of the endometrium, ovary, small bowel, ureter or renal pelvis)
  • Cancer affecting at least two successive generations
  • One person with cancer is a first-degree relative of the other two
  • At least one case of cancer should be diagnosed before the age of 50
  • A diagnosis of familial adenomatous polyposis has been excluded
  • The reported history of cancer has been verified by a pathology report

However, many families with mutations in HNPCC-related genes may be tested without demonstrating all of the above characteristics.*

The majority of HNPCC cases are caused by mutations in one of several mismatch-repair genes: MSH2, MSH6 and EPCAM on chromosome #2, MLH1 on chromosome #3, 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 percent) and endometrial (up to 60 percent) 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, the accumulation 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, which 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, which 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 also is 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 father’s side of the family.

Because of the increased risk of gynecologic cancers in women with HNPCC, these women may want to consider preventative surgery at the time of management of small bowel or colon cancer. Discuss this option further with your doctor or consult a gynecologic oncologist.

* In many cases, tumor tissue from colon and endometrial cancer can be screened for signs of Lynch Syndrome.  This testing for "microsatellite instability," or staining for Lynch Syndrome related proteins, can be helpful for finding Lynch Syndrome even when there is no known family history.