A Genetic Revolution

Date: December 1, 2004

Bert Vogelstein ranks today, as he has for more than a decade, as the pre-eminent international scientist. The discoveries that led the world to understand that cancer is a genetic disease unfolded one by one in his laboratory.

If asked to summarize his work of the last 30 years, internationally renowned cancer researcher Bert Vogelstein would say, “cancer is, in essence, a genetic disease.” It seems like an understatement coming from the most quotable scientist in all of medicine.

But, more than 20 years ago when Vogelstein first cracked open the Pandora’s box that is cancer, revealing first one and then a series of genetic mistakes responsible for colon cancer, it was a foreign concept. Today, his discoveries have led his lab, and others across the country, to develop genetic tests, screening diagnostics, and targeted therapies for colon and other cancers. Ushering in the age of molecular biology, Vogelstein and his co-collaborators, were among the first to apply it to the study of a human disease, developing the knowledge and tools to look inside the submicroscopic molecules of the cell to reveal those rare, uncorrected errors in our DNA that put the cancer process in motion.

The complexity of their genetic discoveries has been likened to finding one two-letter transposition within 20 volumes of “Encyclopedia Brittanica” and then figuring out how it got there. Some scientists consider them to be of the magnitude of finding a cause for polio. But as transforming as these discoveries have been in the cancer world, they started simply and quietly in 1983 in a converted supermarket on the Johns Hopkins East Baltimore Medical Campus.

At the time, all that was really known about colon cancer was that it was an unstable disease that got worse with time. “The man who is really responsible for advancing the understanding of colon cancer is Benjamin Baker,” says Vogelstein. Baker, a Hopkins internist following Vogelstein’s work, was intrigued by this revolutionary concept that cancer was caused by genes gone awry. While others were optimistically in search of the magic bullet that would bring down cancer in one fell swoop, Vogelstein’s studies were revealing a much more complicated disease process. Either through heredity or by assaults from outside forces, genes that serve as counter balances for cell growth (oncogenes that accelerate cell growth, and suppressor genes, which act as a brake keeping cell growth in check) were altered or missing, creating the perfect scenario for cells to grow uncontrollably and form tumors.

Searching for the Errant Genes

Vogelstein quickly began to realize that the tumor itself was just the tip of the iceberg, and what he needed to reveal were the invisible layers beneath the surface that began forming decades before. Baker, who liked Vogelstein’s visionary approach, convinced his wife’s family to donate money from their Clayton Fund to Vogelstein’s lab. This seed money brought together the Bowel Tumor Working Group and would prove to be a turning point in Vogelstein’s research. This collaboration of seasoned clinicians and investigators and young up-and-comers began to shed the first light on the origin of colon cancer and, at the same time, triggered other investigators around the country and the world to look for similar patterns in other cancers.

At first, the discoveries came almost more quickly than they could be sorted out. In 1989, Vogelstein’s identification of p53 mutations in colon cancer started a media frenzy as investigators around the country, following the Vogelstein lab’s lead, found the same mutation in breast, lung, and other cancers. “The p53 gene is the most common gene mutation among all cancers,” the reports read,  and headlines called him “The Man Who May Cure Cancer,” “America’s Hottest Scientist,” and “Mr. P53.” A public eager for a quick fix pinned their hopes on this discovery as the holy grail of cancer. Vogelstein, his own toughest critic, was the first to dash these hopes. While he felt the discovery was important for advancing the science and technology of gene discovery, he was not looking for an answer in one gene. In fact, his lab’s work showed that the p53 alteration was a mutation that occurred late in the cancer process, which led them to the next question. What genetic alterations came before p53?

Inherent Clues

Vogelstein hypothesized that colon cancer resulted from a series of genetic alterations that evolved over decades starting with small clusters of abnormal cells in the lining of the colon, advancing to benign tumors known as polyps, then to a cancerous tumor in the colon, and finally, to where p53 most likely came in, pushing the tumor to its most lethal form, as it spreads outside of the colon to other parts of the body. What Vogelstein wanted to do was identify the whole series of mutations and the order in which they occurred.

He decided to look among the rarest of colon cancers for the answers—inherited colon cancer syndromes. Though they represented the smallest percentage of colon cancers, Vogelstein believed the same genetic underpinnings that led certain families to be plagued by an alarmingly high incidence of colon cancer, and typically at a much younger age, would shed light on colon cancers among the general population. Each of us inherits two copies of every gene from our parents, one from our father and one from our mother. In inherited colon cancer syndromes, family members are born with only one good copy of a gene giving them a headstart on the colon cancer process. As subsequent assaults from diet and other environmental carcinogens knock out the one good copy, the cascade of cellular errors that ultimately results in cancer is put in motion.

Kenneth Kinzler, Vogelstein's research partner and co-director of their lab, pathologist Stanley Hamilton and other members of the Bowel Tumor Working Group were looking for genetic alterations in just such cancers. The Kinzler-Vogelstein team identified a mutation of the APC gene in Familial Adenomatous Polyposis (FAP), a rare inherited syndrome in which affected people get hundreds of benign tumors known as adenomas or polyps in their colons. Further studies showed the same mutation to be the one that jump starts the cancer process in the nearly 140,000 people within the general population who are diagnosed with colon cancer each year.

A Definitive Test

This finding led the gene team to wonder if they could find the mutation in colon cells shed and passed in stool. If they could find APC mutations, the mutations that cause normal colon cells to form the benign polyps that occur before cancer, in cells found in stool, they could potentially prevent the cancer from ever occurring. These studies, first undertaken in 1991 by David Sidransky, who has since moved on to run his own lab using this method to detect cancer-specific DNA in urine, sputum, and other body fluids, has recently been carried forward by Giovanni Traverso and Frank Diehl.

 As investigators explored the potential of fecal DNA as a biomarker for colon cancer, other researchers in the Vogelstein lab were uncovering the genetic culprits of two other inherited colon cancers. In particular, they discovered the genetic and biochemical basis of hereditary non-polyposis colon cancer (HNPCC), which accounts for more than 50 percent of inherited colon cancer syndromes. And in 1998, the team reported a genetic alteration affecting as many as 400,000 people nationwide—6 percent of European descendant Jews (Ashkenazi). Gene testing for cancer was catapulted into mainstream medicine because along with the discovery of the genes that caused these diseases, Vogelstein, Kinzler and colleagues developed tests that would detect the mutations. Such testing is now part of the routine management for patients with strong family histories of the disease, and has dramatically altered how these patients are diagnosed and treated.

Though this research has had major ramifications for patients with hereditary forms of cancer, “heredity plays little if any role in the majority of colon cancer cases,” says Vogelstein. In fact, more than 80 percent of colon cancers strike people with no family history, which brings us back to colon cancer screening using fecal DNA.

“Currently available screening methods for colon cancer are underused, with only a minority of the population taking advantage of them. The best test we have is colonoscopy, but it is an invasive test that scares many people,” says Vogelstein. This has stimulated the Vogelstein-Kinzler group to develop other tests that can detect the disease. The fecal DNA test they are developing is “non-invasive and essentially risk free, and it uncovers the very first genetic event in the colon cancer process,” says Kinzler. This mutation could occur years before an actual cancer develops, giving clinicians ample time to cure or even prevent the cancer from occurring, he adds.

Looking to the Future

Today, Vogelstein, Kinzler, and other investigators are working to advance the fecal DNA test to a stage where it can be used on a widespread clinical basis. Initial studies have shown that the specificity of this test is over 99 percent. In other words, the test does not have false positives, but right now, it misses mutations one third of the time. This is not far off the mark compared to other widely used cancer screening tests, such as mammography or Pap smears. However, the investigators hope to get the sensitivity up to over 80 percent. If such non-invasive tests could be implemented, Vogelstein and Kinzler believe that “colon cancer deaths could dramatically decline.” That is certainly a goal worth shooting for.