Schedule Feb 2, 2005
Genetic Predispositions for Cancers in Humans
Dr. Arnold Levine, IAS

By the decade of the 1960's several different causes of cancer were established but the relationship between these causes remained obscure. An abundance of evidence had demonstrated that viruses, chemicals, genetic alterations and the process of aging could all contribute to the origins of cancers but how these facts could be drawn together in a single unified hypothesis remained unclear. By the 1970's the discovery of cellular oncogenes in retroviruses began the unification of some of these contributors to cancer and in the 1980's the identification of tumor suppressor genes made it clear how germ line mutations lead to cancers at young ages. The decade of the 1990's brought us the elucidation of many signal transduction pathways, composed of oncogenes and tumor suppressor genes that often played a critical role in the development of the organism, and when mutated gave rise to cancers. At the beginning of the 21st century the human genome project provided us with an almost complete list of genes and the genetic polymorphisms in and around these genes that make us different individuals and predispose some to disease processes. Using this information we are now beginning to uncover the how single nucleotide polymorphisms in our genome, along with somatic mutations or viruses, can contribute to the origins of cancer in humans. The lecture will demonstrate how combinations of germ line mutations and polymorphisms in the p53 signal transduction pathway, a tumor suppressor gene that responds to external stress, both increase the frequency and decrease the age of onset of cancers. These observations now unify the roles of viruses, chemicals, genes and aging in the causes of cancers in humans and these conclusions have begun to lead to rational approaches to drug design and the first remissions of cancers without toxicity. We can now see the day when such drugs will be tailored to the genetic background of an individual or a tumor, and positive responses will be observed at higher frequencies. The success of this ration approach in drug design will validate the concepts developed over the past 45 years.

Arnold J. Levine, Ph.D., former president of The Rockefeller University, is a leading authority on the molecular basis of cancer and co-discoverer of the p53 tumor suppressor protein, one of the body's most important defenses against many forms of cancer. Dr. Levine is currently a visiting professor in the School of Natural Sciences at the Institute for Advanced Study in Princeton, New Jersey. Levine was elected to the National Academy of Sciences in 1991 and to its Institute of Medicine in 1995. In April 2001, Levine received the first Albany Medical Center Prize in Medicine and Biomedical Research, the largest annual prize in science or medicine offered in the United States. The prize honors a physician or scientist whose work has led to significant advances in health care and scientific research.

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