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CANCER RESEARCH Vogelstein Launches Center for Cancer BiologyIn 1895, a seamstress who worked for pathologist Aldred Scott Warthin predicted her own death from colon cancer. The woman had never heard of the MSH2 gene or mismatch repair. But so many of her family members had succumbed to the disease that she concluded, correctly, that she would too. A century later, researchers found a telltale genetic deletion in a descendent of the seamstress—the key to what had killed her and her kin.
Bert Vogelstein speaks to an overflow crowd in the TMEC, tracing the history of cancer genetics and describing his new research on chromosomal instability, which he believes may be the origin of colorectal tumors. Photo by Liza Green, HMS Media Services Origins of Cancer GeneticsBert Vogelstein, a Howard Hughes investigator and the Clayton professor of oncology at Johns Hopkins University, told the woman's story in his Nov. 21 lecture inaugurating the Harvard Center for Cancer Biology, the Quad-based portion of the Dana–Farber/Harvard Cancer Center. Vogelstein traced the evolution of colorectal cancer genetics from its prehistory in the 19th century to prospects for prevention in the 21st. Warthin's publication, he said, was the first report of a familial cancer predisposition. A century later, Vogelstein's own landmark studies made him the first scientist to elucidate the molecular basis of the multiple steps of human colorectal and lung cancers.
Vogelstein and coworkers have made major discoveries on each of the two forms of inherited colorectal cancer: familial adenomatous polyposis in which patients develop thousands of tiny, slow-growing polyps, each a potential cancerous tumor; and hereditary non-polyposis colon cancer, in which patients get only one or a few tumors that progress rapidly to malignancy. The Hopkins team discovered that mutations in the APC gene cause the polyposis cancer by interfering with apoptosis. They characterized the non-polyposis form as a failure of DNA mismatch repair leading to genetic instability and have found five different genes involved, including the MSH2 gene that killed Warthin's seamstress. The studies of Vogelstein and other cancer geneticists have focused heavily on families who suffer from inherited forms of cancer. Though these make up only about 15 percent of all cancers, Vogelstein said, they have been invaluable in helping scientists tease out the genetic missteps underlying noninherited cancers, because these are often the same in both groups. "We play a game like 'six degrees of separation' in the lab," he said. "Find a gene and connect it to neoplasia in the fewest possible steps." First Cause of DiseaseA major focus of their recent studies has been chromosomal instability. Most noninherited colorectal tumors do not display the kind of instability at the single-nucleotide level that results from mismatch repair deficiency. What they do show is instability at the chromosomal level, manifested as variously missing or extra copies of whole chromosomes."We believe the first event in colorectal tumorigenesis—perhaps even earlier than APC mutation—is chromosomal instability," Vogelstein said. "What the genes are whose mutations cause this instability, we don't know. But it's a wonderful topic for a combined attack by basic scientists and clinical scientists." The answers will be especially important, he said, because chromosomal instability is found in nearly every major type of cancer. The group's latest findings on chromosomal instability are in press at Nature Biotechnology. For affected families, Vogelstein sees promise in chemoprevention, in which members could take drugs to ward off the development of tumors. His group is now pursuing a combination approach to chemoprevention, using the nonsteroidal anti-inflammatory drug sulindac plus an agent known as EKB569, an inhibitor of the epidermal growth factor receptor kinase. In a study published in the September Nature Medicine, they gave the combination to MIN mice, an animal model for familial adenomatous polyposis. Untreated mice developed an average of 20 polyps, but nearly half the mice treated with the two agents got none at all. —Tom Reynolds |
