Overview
Hereditary nonpolyposis colon cancer (HNPCC) is a heritable type of cancer that affects the digestive tract, most often the colon, as well as the endometrium, ovaries, brain, skin, liver or bile ducts, and the urinary tract. In the United States, 160,000 cases of colorectal cancer are reported per year, and 3 to 5 percent of those are believed to be due to HNPCC according to the National Human Genome Institute.
Genes Involved
Mutations in four genes called MSH2, MLH1, MSH6 and PMS2 have been implicated in 90 percent of HNPCC cases. These genes are called mismatch repair genes because their products are responsible for correcting errors known as mismatches that can occur during DNA replication. Every time that a cell replicates, the DNA must be accurately copied. When mismatches are not corrected, gene mutations can accumulate, which may lead to the development of cancer.
How Mutations Cause HNPCC
Individuals with a mutation in one of the implicated genes have an 80 percent chance of developing HNPCC over their lifetime. Affected individuals usually have one functional copy of the gene and one mutant, non-functional copy. While the functional copy will prevent mismatches at first, the individual can lose this repair function after a random mutation of the working copy. Once mismatch repair is lost, subsequent cell divisions will result in an accumulation of DNA replication errors, some of which will cause mutations that can trigger cancer. Because both a random mutation to the working copy of the gene and specific cancer-causing mutations are needed to develop cancer, not everyone who inherits mismatch repair mutations always gets cancer, they just have an increased predisposition to cancer.
Inheritance
An individual with one mutant copy of an HNPCC-linked gene received that copy from one of their parents. This person has a 50 percent chance of passing the mutant copy on to their children and a 50 percent chance of passing on the normal copy. Because of the familial inheritance pattern of this disease and the 80 percent likelihood of developing cancer when a mutant gene is inherited, it is recommended that relatives of affected family members consult a genetic counselor about testing.
Genetic Testing
While mutations in HNPCC genes can be isolated by genetic testing of a blood sample, these tests are complex and expensive. Candidates for genetic testing are usually first identified because they exhibit a set of characteristics referred to as the Amsterdam II criteria. They can also be recognized using tell-tale changes in specific DNA sequences called microsatellites, which are repetitive DNA sequences prone to change when mismatch repair is inactive. Once a candidate is found, they can go through genetic testing and if a mutation in one of the genes is detected, it can be the target for testing of family members.
Recommended Preventative Measures
Family members of those known to have HNPCC and/or those known to carry a mutant copy of an HNPCC-causing gene are recommended to be routinely screened for developing colon cancer. In their early twenties, at risk individuals should begin regular colonoscopies and any polyps found are usually removed. Because of a relatively high incidence of endometrial and ovarian cancer experienced by those carrying HNPCC-causing mutations, female carriers may also be advised to undergo prophylactic removal of the ovaries and uterus after childbearing is finished.
About this Author
Andrea Todd has a a Ph.D. in molecular biology and genetics from the University of Alberta. Achieved over 18 years, these degrees involved writing accepted peer-reviewed papers (Current Genetics, Genetics, The Plant Journal), a doctoral thesis and an invited book chapter (Plant Epigenetics: Methods and Protocols).
