Public Release: 

Hopkins-HHMI Researchers Discover A Cause And Develop Test For Familial Colorectal Cancer

Johns Hopkins Medicine

Researchers at The Johns Hopkins Medical Institutions and the Howard Hughes Medical Institute (HHMI) have identified the first known genetic mutation that causes familial colorectal cancer (FCC). The mutation causes the cancer through a completely novel mechanism once considered harmless, and is present in over one-half million Ashkenazi Jews, making it the most common cancer-related mutation now known. Using this discovery, researchers have developed a simple blood test to identify the mutation. Their findings are reported in the September 1, 1997, issue of Nature Genetics.

FCC accounts for between an estimated 15-50 percent of all colorectal cancers, but until now its genetic basis has been a mystery, according to Bert Vogelstein, M.D., Clayton Professor of Oncology, HHMI investigator, and co-director of the research. The mutation occurs in a cancer-causing gene called APC, which was previously identified by the same Hopkins researchers and had been linked to a less common form of hereditary colon cancer known as familial adenamatous polyposis (FAP).

The researchers believe that those who have this APC mutation have an estimated 20-30 percent lifetime risk of developing colorectal cancer. "Though they are at increased risk for the disease, it can be detected at an early and curable stage through regular diagnostic screening tests such as sigmoidoscopy and colonoscopy," says Frank Giardiello, MD, associate professor of medicine. Genetic counseling should be provided to all patients tested for the APC mutation, says Giardiello.

The Hopkins team says the newly identified APC mutation and the way it functions are unique. "The mutation itself is harmless. It does not actually change the function of the gene through the loss or insertion of genetic material, as is the case with most cancer-related genetic mutations," says Kenneth Kinzler, Ph.D., associate professor of oncology and co-director of the study. "Instead, what we've found is a subtle alteration in the genetic code that causes DNA instability and leads to hypermutability, or a cascade of mutations in surrounding sequences. These subsequent mutations are what actually causes the cancer," says Kinzler.

Genetic variations such as these, often referred to as polymorphisms, have long been known to researchers, but Vogelstein says they were thought to be junk pieces of DNA that had no bearing on disease. "The new research suggests that many of these polymorphisms will have to be re-examined in future studies to see if they also cause hypermutability," he says.

The researchers first identified the mutation in two unrelated individuals with benign colon tumors and family histories of colon cancer. They went on to study 766 Ashkenazim, believing the genetic similiarity of this group might provide insights into the causes of FCC. In fact, they found the mutation in over 6 percent of those studied.

The researchers then studied blood and tissue samples of 211 Ashkenazi Jewish colon cancer patients. They found that one in six of those patients who developed cancer prior to age 66, and one in eight of those who developed colorectal cancer at any age, had the mutation. The mutation was found in nearly one-third of Ashkenazi patients with a family history of colorectal cancer.

Patients with FCC generally have one or two family members with colon polyps or cancer and typically develop colon tumors in their fifties and sixties. While FCC is believed to account for a larger percentage of total colon cancers occurring in the U.S., it is often difficult to distinguish it from non-hereditary colon cancer. "Until now, its genetic basis has been a puzzle," says Vogelstein.

Although this study and the test are specific to the Ashkenazi Jewish population, the investigators say it provides important clues about familial colorectal cancer among in the general population as well. "Studying specific populations make the discovery of genetic mutations easier. These findings then serve as a paradigm for the general population," Kinzler says. "This is the first example of the kind of mutations that can cause FCC. It will have an important impact on cancer research because it proves that even a subtle alteration--something we used to think was inconsequential--can cause a predisposition to cancer. Now, we must go back and take a second look at things we may have ignored in past," he adds.

More than 130,000 cases of colon cancer are diagnosed in the U.S. each year. At least 15 percent, and perhaps up to half, of these cases are thought to have a hereditary component. FCC is the most common hereditary form. Familial Adenomatous Polyposis (FAP) and Hereditary Non-Polyposis Colon Cancer (HNPCC), two other inherited syndromes well defined by Hopkins researchers in prior studies, account for another 3-5 percent of colon cancers. The remaining cases occur sporadically, with no familial or inherited genetic link, among the general population.

More than 95 percent of the estimated six million U.S. Jews are Ashkenazi. There are over 11.2 million Ashkenazi Jews worldwide, and the researchers estimate that more than 680,000 carry this new mutation. Testing for this specific mutation among this population is currently available at Hopkins. People of Ashkenazi Jewish heritage (typically those Jewish people whose decendents originally lived in Eastern Europe) with at least one first degree relative (a parent, sibling or child) who has had colon cancer and who are interested in more information about the gene test can call 410-955-4041. The gene test costs $200.

In addition to Vogelstein, Kinzler and Giardiello, other participants in this study include, Steve J. Laken, B.A., Gloria Petersen, Ph.D., Stephen B. Gruber, M.D., Ph.D., and Stanley Hamilton, M.D., from Hopkins; Carole Oddoux, B.A., and Harry Ostrer, M.D., from New York University Medical Center; and Heather Hampel, B.A., Arnold Markowitz, M.D., David Klemstra, M.D., Suresh Jhanwar, M.D., Ph.D., Sidney Winawer, M.D., and Kenneth Offit, M.D., from Memorial Sloan Kettering Cancer Center.

The research was funded by the Clayton Fund, the Lucille P. Markey Foundation in Cellular and Molecular Medicine, the National Foundation for Jewish Genetic Disease, the Society of Memorial Sloan Kettering Cancer Center, and the National Institutes of Health.

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Due to licensing and research funding arrangements, the research described here is expected to financially benefit the Johns Hopkins University as well as the authors. Such arrangements are managed by the University in accordance with its conflict of interest policies.

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