Web tool helps gauge risk of having genetic mutation linked to colon cancer

Researchers hopeful that tool's ease of use will lead to early screening for those with elevated risk

BOSTON -- Researchers at Brigham and Women's Hospital and Dana-Faber Cancer Institute have developed an online questionnaire to help physicians determine whether patients at risk for colon cancer are likely to carry mutations in two genes linked to the most common hereditary form of the disease.

The investigators, who report their results in the Sept. 27 issue of the Journal of the American Medical Association, developed the questionnaire based on findings from a five-year study of clinical and genetic data from nearly 2,000 patients. They determined that personal and family medical histories reliably predict an individual's chances of harboring mutations in the cancer-related genes.

The questionnaire, available at http://www.dfci.org/premm and developed from the largest study of these gene mutations in U.S. patients, is one of the first tools with which doctors can quantify patients' likelihood of carrying inherited mutations associated with colon cancer. "We hope the model, and the ease of accessing it on the Web, will lead to healthcare providers being easily able to identify at-risk patients and result in screening at an early age," says Sapna Syngal, MD, MPH, of Brigham and Women's and the study's senior author. "Prevention remains one of our best weapons against colon and other cancers."

The study's lead author is Judith Balmana, MD, formerly of Dana-Farber and currently at the Hospital Vall D'Hebron, Universitat Autonoma of Barcelona, Spain.

Between two and five percent of all colorectal cancers in western countries arise in people with mutations in the genes MLH1 and MSH2 -- a condition called Lynch syndrome. "Our goal was to produce a model that could help doctors quantify a patient's risk of having MLH1 and MSH2 mutations," says Syngal. "Patients at high risk would then be referred for tissue or genetic testing to ascertain whether or not they carry the mutations."

In families with Lynch syndrome (also called hereditary nonpolyposis colorectal cancer, or HNPCC), individuals have an increased risk of developing colorectal cancer, often at an early age. Family members also face a higher-than-average risk for other cancers, including those of the uterine tract lining, ovaries, stomach, small intestines, urinary tract, brain, and skin.

Early identification of people with MLH1 and MSH2 mutations is important because such individuals require a different level of medical management, Syngal notes. Guidelines call for them to receive a colonoscopy every year or two, compared to every ten years for the general population, and they're screened at a more frequent rate for other tumors as well. For some individuals, prophylactic surgeries such as removal of the colon and/or uterus and ovaries may be recommended.

For the current study, Myriad Genetic Laboratories, Inc., of Salt Lake City, provided Syngal and her colleagues with genetic test results from blood samples of 898 patients at risk for colon cancer, along with information on the medical history of the patients and their families. All potentially identifying information had been removed from the data to protect patient anonymity. Investigators matched the samples that tested positive for MLH1 and MSH2 mutations with patients' reports of their medical history. (The reports came from healthcare providers, not patients.)

"We found a close correlation between patients and their families' history of colon and other HNPCC-related cancers and the presence of the two gene mutations," says Syngal, who is also an assistant professor of medicine at Harvard Medical School. After researchers developed the questionnaire model, they validated it with data from an additional 1,016 patients.

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Funding for the study was provided by grants from the National Cancer Institute, "La Caixa" of Barcelona, Spain, the Trust Fund of Erasmus University in Rotterdam, Dana-Farber, and the American College of Gastroenterology.

The study's co-authors are David Stockwell, MD, MPH, of Brigham and Women's Hospital; Ewout Steyerberg, PhD, of Dana-Farber and the Department of Public Health, Erasmus MC, in Rotterdam, Netherlands; Elena Stoffel, MD, MPH, of Brigham and Women's; and Amie Deffenbaugh, Julia Reid, Brian Ward, PhD, Thomas Scholl, PhD, Brant Hendrickson, John Tazelaar, MD, and Lynn Anne Burbidge of Myriad Genetics.

Brigham and Women's Hospital is a 747-bed nonprofit teaching affiliate of Harvard Medical School and a founding member of Partners HealthCare System, an integrated health care delivery network. BWH is committed to excellence in patient care with expertise in virtually every specialty of medicine and surgery. The BWH medical preeminence dates back to 1832 and today that rich history in clinical care is coupled with its national leadership in quality improvement and patient safety initiatives, dedication to educating and training health care professionals, and strength in biomedical research. With $370M in funding and more than 500 research scientists, BWH is an acclaimed leader in clinical, basic and epidemiological investigation - including the landmark Nurses Health Study, Physicians Health Studies, and the Women's Health

Dana-Farber Cancer Institute (www.danafarber.org) is a principal teaching affiliate of the Harvard Medical School and is among the leading cancer research and care centers in the United States. It is a founding member of the Dana-Farber/Harvard Cancer Center, designated a comprehensive cancer center by the National Cancer Institute.


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