Gene causing colon cancer found Discovery at Hopkins expected to save thousands of lives

THE BALTIMORE SUN

Scientists in Baltimore and Finland have found evidence of a gene that causes a common form of colon cancer, and expect soon to offer a test that will tell members of families plagued by the disease if they, too, will get it.

The discovery, perhaps the high point of a decade of groundbreaking research at the Johns Hopkins Oncology Center, could save thousands of lives annually in this country alone by giving people the ability to foretell their cancer future -- and do something about it.

The gene predicts colon cancer with almost cruel certainty: People who carry it run about a 95 percent chance of developing the disease sometime in their lives, said Dr. Bert Vogelstein, who directed the research at Hopkins. The gene also increases a person's chance of developing cancer of the uterus, ovaries, stomach, kidneys, small intestine and gallbladder.

Once people learn that they carry the genetic defect that causes colon cancer, they can get examined regularly for signs of a developing tumor, said Dr. Vogelstein. This, in turn, will give doctors a chance to detect the cancer in time to cure it.

"It's so important to know because you can actually do something about it," said Dr. Vogelstein. "It's not just something to wring your hands over. If you detect it early enough, it can be cured."

More than 90 percent of patients survive colon cancer for at least five years if their tumors are confined to a small area. But the five-year survival rate drops to less than 2 percent when the cancer has spread throughout the body.

Doctors look for signs of a developing tumor by examining the colon with a long, flexible scope. The common treatment is surgical removal, sometimes combined with radiation or chemotherapy.

The scientists, Dr. Vogelstein and Dr. Albert de la Chapelle of Helsinki, Finland, estimated yesterday that the susceptibility gene is carried by one in every 200 people. This makes the disease the most common inherited illness yet known -- 10 times more common than cystic fibrosis and 25 times more frequent than muscular dystrophy.

But the discovery, and the test it yields, could be a blessing for people who have watched close relatives suffer and often die of colon cancer. A positive test means they can watch for the disease and catch it early; a negative test could spare them years of worry.

"We see patients who are 25, 30, 35 years of age come in with untreatable colon cancer, untreatable uterine cancer," Dr. Vogelstein said yesterday at a news briefing in Washington arranged by the American Association for the Advancement of Science, which publishes the journal Science.

"We now have a completely novel way of taking care of these families. We can tell who is going to get it and who is not. We can institute appropriate preventive measures for those who are going to get it. And the others can breathe a huge sigh of relief," he said.

A report on the discovery appears in this week's edition of Science.

The gene is responsible for one in seven cases of colon cancer; the rest are caused by genetic damage that occurs after birth. In a family afflicted by the hereditary disease, one in four people will inherit it.

Dr. Vogelstein said the genetic test should be available within six months for people who have strong family histories of colon cancer -- more than three close relatives with colon cancer. Within two years, he said, the test should be ready for families in which two or three members have been diagnosed.

The test will cost an average of $500 for each family tested, he estimated. "We'll take the whole family group and test everybody," he said.

It is doubtful that it will ever become a screening tool for the general population because the gene is prevalent only in families with histories of colon cancer, he said. But he said it would also be appropriate for families that have histories of both colon and uterine cancer -- or both colon and ovarian cancer.

Colon cancer claims 60,000 lives in the United States each year, making it the most lethal of all cancers except lung cancer. Dr. Vogelstein said the inherited form is probably responsible for 5,000 to 10,000 of these deaths.

Over the last decade, Dr. Vogelstein's laboratory showed that most colon cancers are triggered by an accumulation of four genetic defects -- or mutations -- that occur during a person's lifetime.

Three of these defects rob "suppressor genes" of their ability to put the brakes on cancer, which is the uncontrolled growth of cells. A fourth causes a growth-factor gene to go on overdrive, encouraging cells to replicate much faster than they should. Cancer does not develop until the entire sequence of mutations is complete, which explains why most patients do not get the disease until their 50s or 60s.

But Dr. Vogelstein said he was surprised to learn that a "novel mechanism" causes the inherited form: A single gene, passed from parent to child, accelerates the cascade of genetic accidents needed to trigger cancer. With this inheritance, a person can get colon cancer two or three decades earlier.

Scientists had long observed that colon cancer can run in families. But the suspicion wasn't proved until researchers at the Johns Hopkins Oncology Center and the University of Helsinki started examining the blood samples of several extended families in which the disease is rampant.

Starting four years ago, they employed the new tools of molecular genetics to see if they could find a common "marker" in the genetic material of family members who had suffered from the disease. It's a laborious process, like searching a network of highways for a single pothole.

More than three years passed before they found anything. The possibility always remained that a common diet or environmental factor caused the disease to cluster in some families.

"When you're not sure if it's something that has a heritable basis, you have to wonder if you're wasting your time," Dr. Vogelstein said. Finally, they discovered the genetic marker on the second chromosome. (Each cell has 23 chromosome pairs).

"This information will be most useful in identifying people who are predisposed -- those who do not have colon cancer but five, 10, 20 years from now will have high likelihood of developing colon cancer," said Dr. Curt Harris of the National Cancer Institute.

John Velthuis, a 37-year-old Savage resident who was diagnosed with colon cancer a year ago, said he intends to have his three children tested for colon cancer. His sister and grandmother died of it, and his father suffered from it before dying of an unrelated illness.

Mr. Velthuis said the cancer was probably growing for several years before he felt his first symptoms, stabbing pains in his abdomen. By then, the tumor had grown as large as a softball. He had it removed, and has been undergoing chemotherapy for a year. Doctors told him the tumor had not spread, and his survival chances are good.

"With the test, my children won't have to go through what I've gone through -- a totally miserable experience the last year of my life," Mr. Velthuis said.

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