"Inactivating a tumor suppressor gene is like disabling the brakes on a car," says the study's corresponding author, Eric Green, M.D., Ph.D., chief of the Genome Technology Branch in the NHGRI Division of Intramural Research. "Without the function of such a gene, a tumor keeps growing out of control. And just like a car without brakes, the consequences can be fatal."
In the new study, published in the April issue of Nature Genetics, the researchers reported finding the new gene, which they named ST7, short for Suppression of Tumorigenicity 7, on chromosome 7. Studies show that the gene is widely expressed in normal tissues throughout the body and that the gene is often disrupted by mutation or deletion in tumors arising from epithelial cells, such as cancers of the breast, prostate, colon and ovary.
Scientists know of at least 30 tumor suppressor genes and a search of gene databases suggests that there may be another 100 or more. So finding a new one alone is not surprising. But the discovery of ST7 demonstrates a new paradigm in molecular genetics research now that the first draft sequence of the entire human genome is available. In the past, the discovery of a new tumor suppressor gene would require a major effort involving many scientists, often in several laboratories, working for several years. ST7 was discovered by a single post-doctoral scientist using the new tools provided by the Human Genome Project.
"This finding is an excellent example of how individual researchers, aided by the availability of the near-complete sequence of the human genome, can make major advances in our knowledge of the genetic basis of disease in a matter of a few years or less," says NHGRI Director Francis S. Collins, M.D., Ph.D.
The finding also shows how the information in the human genome sequence enables scientists in different fields to make research contributions far beyond their own specialty, says NHGRI scientific director Jeffrey M. Trent, Ph.D. "Dr. Green's laboratory has been heavily involved in mapping and sequencing human chromosome 7 for the Human Genome Project," he says. "In the last four years, Green's lab directly participated in the identification of genes involved in deafness, vascular disease, and now cancer."
The current research began in 1993 with the doctoral studies of lead author Jean Claude Zenklusen, Ph.D. While working in the lab of co-author Dr. Claudio Conti at the M.D. Anderson Cancer Center's Department of Carcinogenesis, Zenklusen generated a large body of evidence that the long arm of chromosome 7 harbored a tumor suppressor gene. After moving to NHGRI in 1996, Zenklusen began using the genetic maps and DNA sequence of chromosome 7 that were provided by the Human Genome Project. Using a technique called positional cloning, Zenklusen narrowed down his search to a few genes. He then pain-stakingly studied each gene for mutations in cancer cells and found defects in ST7 in several instances. The study included several functional analyses, such as one in which Zenklusen inserted a normal copy of the gene into tumor cells with defective ST7. The genetic treatment eliminated the cancer cells' ability to produce tumors in mice.
The researchers still don't know exactly what the gene does. "ST7 has no relatives or structural similarities to any other known gene," Zenklusen says. But the scientists have shown that the gene has been highly conserved over evolution, since it is widely found in lower organisms. That generally means the gene plays an important function in the body.
Preliminary evidence suggests that ST7 may be involved in regulating the growth of blood vessels into a tumor, a process called angiogenesis. "If ST7 is involved in regulating angiogenesis, it may prove to be a target for developing drugs that would interfere with that process," Zenklusen says. "Without an adequate blood supply, a tumor withers away and dies. So theoretically, if you could prevent angiogenesis, you might be able to come up with a way to kill the tumor without harming the patient."
Zenklusen, Conti and Green, are co-authors of the paper, "Mutational and functional analyses reveal that ST7 is a highly conserved tumor suppressor gene on human chromosome 7q31," which appears in the April issue of the journal Nature Genetics (Vol. 27, No. 4).