Molecular Basis of Colon Cancer
Bert
Vogelstein, M.D.—Investigator
Bert Vogelstein, M.D.—Investigator
Dr. Vogelstein is also Clayton Professor of Oncology, with a joint
appointment in Molecular Biology and Genetics, at the Johns Hopkins University School of
Medicine. He received a B.A. degree in mathematics from the University of Pennsylvania and
an M.D. degree from the Johns Hopkins University School of Medicine. Following internship
and residency at the Johns Hopkins Hospital, he performed postdoctoral research at the
National Cancer Institute. Dr. Vogelstein has received numerous national and international
awards for his research and is a member of the American Academy of Arts and Sciences, the
National Academy of Sciences, and the American Philosophical Society.
TUMORS of the colon are a major health problem: more than half of the United States population develop at least one such tumor, and in one-tenth of these individuals the tumors progress to malignancy. New ways of preventing and treating these tumors are desperately needed. Our research is aimed at understanding the molecular basis of colon neoplasia, in the hope that the knowledge gained can eventually be applied to patient care.
The steps to colon cancer are driven by sequential mutations in genes of three classes. The first class, oncogenes, are the cells' accelerators, controlling growth in a precisely balanced fashion. Mutations in oncogenes are tantamount to having the accelerator locked in the "on" position. But cells also have brakes, the tumor-suppressor genes. Normally these brakes can stop runaway cells from dividing, but mutations can render the brakes dysfunctional. As each oncogene or tumor-suppressor gene is sequentially mutated, a stage of tumor initiation or progression ensues. It is only when several of the cell's accelerators and brakes are altered by mutation that a malignancy forms.
A third class of cancer-causing genes, the mutator genes, was more recently discovered. These genes do not intrinsically control cell growth, but simply control the rate of mutations of other genes, including oncogenes and tumor-suppressor genes. Aberrant mutator genes thereby cause a high rate of mutation, which accelerates tumor progression.
Colon cancers, like those of many other organs, occur at elevated frequency in certain families. Work in our laboratory and others has demonstrated that affected members of such families inherit abnormal mutant genes that are responsible for tumor predisposition. Two different kinds of genes have been shown to cause most hereditary colon cancer cases.
Knowledge of the genetic basis of FAP and HNPCC provides new opportunities for more-effective management of the millions of families with these diseases. We have developed an animal model of FAP in which the genetic and biological components are similar to those of humans. These animals are being used to test chemopreventive agents. Methods to identify affected members of families efficiently are another major component of our work. We recently developed a blood test that appears useful in this regard for FAP patients. Nucleic acids are purified from blood cells and, following the enzymatic amplification of APC sequences, translated into protein. This test has a specificity of virtually 100 percent and a sensitivity of 85 percent. HNPCC can be caused by any of several genes; the development of diagnostic tests poses a difficult challenge, which our laboratory is pursuing.
As noted, colon tumors progress through a series of steps, each associated with a specific mutation. Although a mutation can be inherited (as in FAP), in most cases all mutations are somatic; that is, they occur in single cells as a result of mistakes made during DNA replication or through exposure to dietary mutagens. The sequence of acquisition of these mutations is critical. APC mutations, acquired through hereditary or somatic means, appear to initiate all colorectal tumors. Subsequently, somatic mutations in the K-ras oncogene and DCC and p53 suppressor genes cause the tumors to progress to the malignant state.
The p53 gene can dramatically inhibit the growth of cancer cells when introduced by gene transfer. This suggests that targeting p53—through gene therapy or other novel approaches—could bring a new dimension to cancer treatment. Current work in our laboratory is in part focused on further understanding the pathways through which p53 acts, with the expectation that this research will point the way toward future therapeutic applications.
Grants from the National Institutes of Health provided partial support for the studies described above.