New Gene Mutation Identified In Colon Cancer

NEW YORK - A newly identified genetic mutation may account for up to nine percent of the colon cancer cases diagnosed in the United States, report scientists at Memorial Sloan-Kettering Cancer Center and other research centers in the November 15 issue of Cancer Research. The gene mutation was also found in several other types of cancers as well as in healthy individuals.

"The two significant aspects of this finding are the relatively high frequency of this mutation in the general population, and the identification of a new mechanism that may result in increased risk for cancer," said Kenneth Offit, M.D., Chief of the Clinical Genetics Service at Memorial Sloan-Kettering, and a senior author of the study.

To test the hypothesis that the newly identified mutation, called TbR-1(6A), might play a role in the development of cancer, the investigators evaluated blood samples taken from 851 cancer patients and compared them to blood samples collected from 735 healthy volunteers. Of the 112 patients with colon cancer, 21 were found to have either one or two copies of the mutation. Extrapolating these findings to the general population, researchers estimate that this mutation could account for about 10,000 of the 111,000 cases of colon cancer diagnosed in the U.S. each year.

In addition, the investigators found that 123 cancer patients and 78 healthy individuals had a single copy of the mutation. This means that there is a relatively high frequency of this mutation -- about 10 percent -- in the general population.

Researchers found the most significant risk for developing cancer in individuals who inherited a copy of the mutation from both parents. Among the cancer patients, nine carried two copies of the mutation. In contrast, none of the healthy volunteers carried two copies of the mutation.

"To find this number of people in the cancer group who carried two copies of this mutation and no such individuals among the healthy controls is striking evidence for the cancer risk that results," said Boris Pasche, M.D., Ph.D., a post doctoral researcher at Memorial Sloan-Kettering and lead author of the study.

Among the nine patients who had both copies of the mutation, four had colon cancer, two had testicular cancer, and the remaining three individuals had ovarian cancer, lymphoma, and lung cancer, respectively.

"In contrast to other syndromes associated with susceptibility for breast or colon cancer, this study shows that an individual must inherit one copy of this mutation from both parents in order to have the most pronounced risk for cancer," said Dr. Offit. "However, because the frequency of the mutation in the general population is relatively high, this may be one of the more common colon cancer risk factors."

TbR-1(6A) is a mutant form of the receptor for a molecule called Transforming Growth Factor Beta (TGF-b). TGF-b signals cells when to stop growing. In the development of cancer, tumors lose the ability to respond to TGF-b and continue to grow uncontrollably. In this study, investigators examined how the mutation might interfere with the activity of TGF-b to inhibit the growth of cancer.

"We found that the mutation slightly weakened the receptor and therefore cancer cell growth was not normally suppressed by TGF-b," said Joan Massague, Ph.D., a senior author of the study and Program Chairman of Cell Biology at Memorial Sloan-Kettering. "We have known of genetic alterations that directly cause a disease, but we are beginning to recognize that the different susceptibility of individuals to cancer may have to do with the presence or absence of subtle genetic differences," said Dr. Massague.

The investigators plan to conduct additional follow up studies to determine how likely individuals who carry the mutation are to develop colon cancer, or pre-cancerous lesions called polyps. These lesions may be found and removed by screening procedures such as colonoscopy, offering the promise of improved cancer surveillance and detection. The authors caution that testing for this mutation should only be performed in research studies, since medical and family history are still the best guides to cancer screening.

Memorial Sloan-Kettering Cancer Center is the world's oldest and largest private institution devoted to prevention, patient care, research, and education in cancer. Throughout its long distinguished history, the Center has played a leadership role in defining the standard of care for patients with cancer. In 1999, Memorial Sloan-Kettering was named the nation's best cancer care center for the seventh consecutive year by U.S. News and World Report.