March 29, 1995
Media Contact: Karin Twilde or Kate Ruddon
Phone: (410) 955-1287
E-mail: krudden@welchlink.welch.jhu.edu

Researchers in the Johns Hopkins Medical Institutions departments of pathologyand oncology have identified the genetic cause of Turcot's Syndrome, a condition characterized by brain and colon tumors. Their findings are reported in the March 30, 1995 issue of The New England Journal of Medicine.

This new genetic evidence linking the two cancers may mean that Turcot's Syndrome is much more common than the medical literature indicates, according to the researchers. "These findings have given us completely new information about the causes of brain tumors and allow for diagnosis of the syndrome based on molecular genetic characterization," says Stanley R. Hamilton, M.D., professor of pathology and oncology who directed the study.

The research team studied 14 families with a history of both colon and brain tumors who were enrolled in hereditary colon cancer registries at Johns Hopkins and Mount Sinai Hospital in Toronto. The investigators found mutations in two types of genes known to cause inherited forms of colon cancer. Ten of the families had alterations of the APC gene, a tumor suppressor gene associated with Familial Adenomatous Polyposis (FAP), a disease in which those affected get hundreds to thousands of small benign colon and rectal tumors called adenomatous polyps which eventually progress to cancer. In two additional families, the scientists identified a mutation of one of two mismatch repair genes, hMLH1 or hPMS2. Mismatch repair genes act as proofreaders, looking for mistakes in the DNA copying process and correcting them. People who inherit a defective mismatch repair gene tend to be mutation-prone and are at higher risk of developing cancer. Both hMLHI and hPMS2 are involved in the development of another type of colon cancer known as Hereditary Non-Polyposis Colorectal Cancer (HNPCC), believed to be the most common inherited disease in humans.

"We've known from the literature that people with FAP have a higher incidence of brain tumors, but we didn't know how the two were related. No data prior to this, however, have ever indicated a relationship between HNPCC and brain tumors," says Dr. Hamilton. The Hopkins researchers determined that people with FAP are about 90 times more likely to develop brain tumors than the general population. They are currently attempting to calculate the risk for people with HNPCC.

The first documented cases of Turcot's Syndrome date back to 1959, when French-Canadian doctor Jacques Turcot and colleagues identified colon and brain tumors in a teenage brother and sister. Since that time, approximately 120 cases resembling these original patients have been reported, but the relationship of FAP to Turcot's Syndrome was controversial.

The Johns Hopkins team collaborated with a researcher from Hotel-Dieu de Quebec Hospital to obtain the pathology slides containing tissue samples from these first documented cases. When they examined DNA from the tissue samples, they found evidence of mutation of a mismatch repair gene in both the brain and colon tumors.

"Historically, Turcot's Syndrome has denoted the presence of colon polyposis and a primary tumor of the central nervous system," Hamilton says. "This new evidence indicates that people who inherit defective copies of either of the two types of genes are predisposed to colon and brain cancer, and potentially a number of other cancers as well."

Those affected rarely develop both cancers, however, he notes. Some may have only colon cancer, while others may develop only brain tumors. Several of the families studied had members who died of brain tumors with no evidence of colon polyps or cancer. Further investigation, however, identified evidence of FAP or HNPCC in the family. Studies are now underway to look for APC or mismatch repair gene mutations in additional brain tumor patients with a family history of colon cancer to determine if they have Turcot's Syndrome.

A simple blood test which could be used in high risk families to identify family members with the genetic alterations is under development. Those that test positive can be followed closely by their physicians and take advantage of available screening test.

Turcot's Syndrome patients in this study lived at least three years, and one is a 14-year survivor. Patients with malignant brain tumors rarely survive more than one year. Experts do not know why patients with Turcot's Syndrome tended to survive longer with their brain cancers than patients with sporadic brain tumors.

The research was funded by a National Cancer Institute Gastrointestinal SPORE grant. Other participants in the research included Bo Liu, Ph.D., Ramon E. Parsons, M.D., Ph.D., Nickolas C. Papadopoulos, Ph.D., Jin Jen, Ph.D., Steven M. Powell, M.D., Anne J. Krush, M.S., Theresa Berk, M.S.S.A., Zane Cohen, M.D., Bernard Tetu, M.D., Peter C. Burger, M.D., Patricia A. Wood, M.D., Ph.D., Fowzia Taqi, M.D., Susan V. Booker, B.A., Gloria M. Petersen, Ph.D., G. Johan A. Offerhaus, M.D., Anne C. Tersmette, Ph.D., Francis M. Giardiello, M.D., Bert Vogelstein, M.D., and Kenneth Kinzler, Ph.D.

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