Hereditary nonpolyposis colon cancer (HNPCC) is a form of inherited colon cancer which usually presents with a few to less than 50 polyps. It has been defined for research purposes (known as the Amsterdam Criteria) as a family with at least three cases of colon cancer, at least one of which is diagnosed by 50 years of age, and in which individuals are affected in at least two generations. However, it is known that a number of other cancers are also at increased risk in HNPCC gene carriers, including endometrial and ovarian cancer in women, and stomach, pancreatic, small intestine, biliary tract, ureter, and renal pelvis cancers in both men and women. Recently, revised Amsterdam Criteria have been adopted which allow for the inclusion of these other HNPCC-related cancers, in addition to colon cancer. The lifetime colon cancer risk in HNPCC is estimated to be between 80 and 90 percent, while the risk for endometrial cancer in women is about 40 percent. The other cancers occur at significantly lower rates.
Mutations in at least five different genes have been shown to cause HNPCC. Two of these (MLH1 and MSH2) account for the majority of cases, and can be analyzed on a commercial basis. MLH1 and MSH2 mutations are found in about 70 to 80 percent of families meeting Amsterdam Criteria, but in only about 10 to 30 percent of families with evidence of hereditary cancer but not meeting Amsterdam Criteria. MSH6 has recently been found to account for approximately 10 percent of cases of HNPCC. MSH6 mutations may cause colon cancer at a later age of onset than MLH1 and MSH2. Therefore, families who do not meet the Amsterdam criteria may have mutations in MSH6.
In addition, tumor tissue from most (80 to 90 percent) individuals with HNPCC show an abnormality in the copying of the genetic material (DNA). This abnormality is called micosatellite instability (MIS) by some groups and replication error (RER+) by others. Testing for MIS/RER can be used as a cost effective screen to assess whether HNPCC gene studies are indicated, since patients with an MIS negative tumor tissue are unlikely to test positive for an HNPCC gene mutation. However, about 10 to 15 percent of non-HNPCC tumors will also test positive. Testing for the two major HNPCC genes costs approximately $1500 to $2700, depending on the laboratory used. Analysis of tumor tissue for MIS/RER costs approximately $300 to $500. Children (under 18) will not be tested for HNPCC mutations since it will not affect their medical management.
HNPCC is inherited as an autosomal dominant condition. This means that each child of an individual having one of these gene mutations has a 50 percent chance themselves of inheriting the mutation. Genetic testing is available which can identify mutations in many, but not all, families with hereditary colon cancer. We emphasized that because of limitations in the technology, failure to detect a mutation in a family does not rule out hereditary cancer. If a mutation is identified in an affected individual in a family, at-risk family members can be tested with nearly 100 percent accuracy. Those relatives inheriting the mutation face increased cancer risks, and should be followed appropriately. Relatives who have not inherited the gene mutation are at no increased risk for cancer over the general population.
Guidelines for HNPCC patients call for colonoscopy every 1 to 2 years (every year following detection of an adenoma) starting at age 25 (or 5 years before the earliest colon cancer diagnosis in family, if it was under age 30). All adenomas are removed, and removal of the colon by subtotal colectomy is generally performed if cancer is found, with continued screening for rectal cancer. Some centers consider offering prophylactic subtotal colectomy. Women should also receive an annual pelvic exam, transvaginal ultrasound and CA 125 blood testing, starting at 25 to 30 years old, for ovarian cancer; and annual ultrasound/endometrial aspiration biopsy after age 30 for endometrial cancer. Some programs consider prophylactic removal of the uterus and/or ovaries if a strong family history of these cancers is present. Men and women should also be examined for other HNPCC-related cancers if present in the family (stomach: gastroscopy q 1 to 2 years, starting at age 30; urinary tract: ultrasound q 1 to 2 years, starting at age 30 and urine analysis). At-risk family members generally undergo colonoscopy every two to three years, starting at age 25, with screening for other HNPCC-related cancers if they are present in the family. At-risk women should be screened for gynecologic cancers with the same protocol as HNPCC patients.