Colon cancer is a terrible scourge. It strikes more than 155,000 Americans each year. And with an annual death toll in the U. S. of 60,000, it's second only to lung tumors as a killer of cancer victims. That's why scientists have been probing genes in an effort to find the fatal strands of DNA that lead to colon tumors. Over the past few years, they've identified three of the genes that, when altered, are cancer time bombs. Now, two research teams may have nabbed the trigger gene, the one that touches off the cascade of changes on the cellular road to cancer.
Once scientists figure out how the newly identified gene brings on the deadly process, they may be able to design drugs that can block the chain of events. That could dramatically reduce the death rate from the disease, which now is treated with the standard "cut, burn, and poison" approach of surgery, radiation, and chemotherapy.
The discovery, announced on Aug. 9 in a series of scientific papers in the journals Science and Cell, also comes with a darker side. Scientists think that the flawed gene is inherited by one in 5,000 people. And they are devising ways to search for it even before birth. "It brings up a whole set of troubling ethical questions," says Johns Hopkins University oncologist Bert Vogelstein, leader of one of the teams.
ALTERED STATES. Identifying the gene, named APC for adenomatous polyposis coli, highlights the remarkable progress science has made in understanding the genesis of cancer. It turns out that colon cancer is an ideal candidate for scrutiny because it occurs in several distinct stages. The first is the growth of tiny lumps or polyps in the lining of the colon or rectum. Former President Ronald Reagan made this condition famous in 1985, but doctors estimate that 40% of us will have one or more polyps at some point in our lives. Fortunately, only 10% of those with polyps will progress to the next stage of the disease, when the polyps turn into malignant tumors. The final stage occurs when the tumor cells spread beyond the colon to other parts of the body.
Researchers, including Vogelstein and Raymond White at the University of Utah, have been able to show that different genes act at different stages of the disease. Most of the genes previously identified seem to play a role in the final stages. When altered, they cause a benign polyp to turn into a malignant tumor and spread throughout the body (table).
APC seems to control the crucial first step to colon cancer. The evidence is twofold. First, after years of genetic sleuthing, White was able to show that the gene was linked to an inherited disease called familial adenomatous polyposis, or FAP. By the age of 30, victims typically grow a veritable carpet of polyps in their colons and must have the organ removed. By testing the DNA in large families with the disease, White discovered that many of the victims had inherited flawed copies of the APC gene.
The second key piece of evidence comes from Vogelstein's group. The Johns Hopkins researchers found flawed versions of the APC gene in polyps and tumors sliced from people who get the more common, nonfamilial form of the disease. What apparently happens is that the gene can mutate, due to a variety of environmental factors--from exposure to specific chemicals or radiation to the accumulated defects of the aging process. The result is a biochemical change that leads to polyps.
The crucial question that remains is why alterations in the gene set off the series of steps leading to cancer. To answer that, scientists must find out what the correct version of the gene normally does. "The function of the gene is almost a totally open question," says Vogelstein.
TESTING AND ETHICS. Turning the discovery into new therapies also will await a better understanding of how the gene works. But, White notes, for families affected by FAP, doctors will soon be able to tell who has inherited the gene. The notion of testing the unborn for the gene--or other genes that predispose people to cancer--raises such troubling questions as whether parents will want to give birth to children who have a good chance of developing cancer at an early age. In addition, there's worry that people with these genes won't be able to afford health insurance. But for people at risk for noninherited colon cancer--usually because they eat lots of fat--a diagnostic test could be a lifesaver. "Early diagnosis is very important, because only by removing polyps can you reduce the chance of cancer," says White.
For many researchers, colon cancer is just a first step. They believe that some of the same or similar genes are the culprits in other stubborn cancers such as those of the breast and lung. And as they begin to unlock this deadly mystery, they are getting closer to stopping cancer where it starts.
THE CULPRITS IN COLON CANCER Researchers believe that anywhere from 6 to 10 different genes may be involved in the progression of colon cancer. The following four have been identified so far Gene Role in disease APC Formation of polyps RAS Transformation of polyp to tumor DCC Late-stage malignant tumor P53 Malignant tumor and spread of cancer DATA: BW