July 21, 1999
Study offers guidelines for genetic testing for Colorectal Cancer
Although colorectal cancer rarely stems from an inherited mutation of a gene, an increasing number of clinics now offer tests for determining whether families with a history of colon cancer carry a mutation that predisposes them to the disease. The novelty of such tests, combined with frequent ambiguities in the test results, can make it difficult for physicians to interpret the tests and advise at-risk individuals on an appropriate course of care.
In a study in the July 21st issue of the Journal of the American Medical Association, researchers at Dana-Farber Cancer Institute and Brigham and Women's Hospital report that for some colon cancer-prone families - specifically those found to harbor harmful genetic mutations - genetic testing does indeed offer a valuable way of identifying individuals at risk for the disease. Families for whom the tests do not yield definitive results - the majority of those tested - should still be especially vigilant about monitoring their health and undergoing diagnostic tests to detect cancer in its earliest stages, the authors advise.
The study involved a condition called hereditary nonpolyposis colorectal cancer (HNPCC), a rare syndrome that increases people's lifetime risk of colorectal, uterine, and cervical cancer, as well as cancers of the gastrointestinal and genitourinary tracts. "Only five to 10 percent of all cases of colon cancer result from inherited gene mutations," says the study's senior author, Judy Garber, M.D., M.P.H., director of the Cancer Risk and Prevention Clinic at Dana-Farber. "Even though HNPCC is the most common form of inherited colon cancer, it still represents only a small fraction of all the cases of the disease that occur."
HNPCC can be an elusive condition to diagnose. "When two or three members of a family develop colon cancer, it's not always clear whether it's a coincidence or a result of an inherited mutation," Garber says.
It was to help clarify such situations that genetic testing for HNPCC has been introduced at many clinics around the country. The tests look for mutations in two genes, hMSH2 and hMLH1, that are known to be associated with HNPCC. However, the interpretation of these tests is not always straightforward.
"We know of about 100 mutations to hMSH2 and hMLH1 that can give rise to hereditary nonpolyposis colorectal cancer," says the study's lead author, Sapna Syngal, M.D., M.P.H., of Dana-Farber and Brigham and Women's Hospital. "We also know of mutations to the genes that don't seem to have any connection to the condition. To complicate matters even further, there are known to be three other genes whose mutations are involved in HNPCC. All of these factors limit the usefulness of current genetic screening tests for the condition."
In the study, researchers performed genetic tests on 70 families with HNPCC. They found that 18 of the families - or 26 percent - had mutations that were definitively linked with HNPCC. Previous studies have shown that people with such mutations have an 80 percent risk of developing colorectal cancer. The rest of the families either had no discernible mutations in those genes or had mutations that could not clearly be shown as the cause of colorectal and related cancers.
The researchers conclude that for families found to carry harmful mutations to hMSH2 and hMLH1, genetic testing is indisputably useful. Family members with such mutations should receive frequent diagnostic tests for colorectal and related cancers and may wish to consider pre-emptive surgery - such as removal of the colon, uterus, or ovaries - to prevent a cancer occurrence, researchers suggest.
In families where harmful mutations are not discovered, or where mutations are not clearly linked with disease, careful monitoring of health is called for, and frequent diagnostic tests to catch any cancers in their earliest stages, when they are most easily treated.
"The limitations of current genetic screening tests for HNPCC mean that doctors and patients need to be very careful in interpreting test results," Syngal says. "At a time when such tests are still being refined and improved, our study provides reasonable guidelines for doctors and patients in sorting through their options."
