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Cancer Research Pioneer Explores Epigenetic-Environmental Connections

By Eddy Ball
March 2007

Steven Baylin
Guest Lecturer Steven Baylin (Photo courtesy of Steve McCaw)

Paul Wade
Lecture host Paul Wade (Photo courtesy of Steve McCaw)

Lamia Benbrahim-Tallaa, Chris Geyer and Bob Langenbach
Shown in the audience from left to right are NCI Fellow Lamia I. Benbrahim-Tallaa, Ph.D. (on detail to the Environmental Toxicology Program), Laboratory of Reproductive and Developmental Toxicology Fellow Chris Geyer, Ph.D., LMC Microbiologist Bob Langenbach, Ph.D., and LMC Special Volunteer Barbara Burkhart, Ph.D. (Photo courtesy of Steve McCaw)

Stephen B. Baylin, M.D., presented the latest talk in the 2006-2007 Distinguished Lecture Series on February 13 in Rodbell Auditorium. Baylin is professor of medicine and oncology at the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University. The topic of his lecture was "Cancer: The Environment and the Epigenetic Interface."

In his introduction, lecture host Paul Wade, Ph.D., an investigator in the Laboratory of Molecular Carcinogenesis (LMC), described Baylin as "a true pioneer in his field." "He has continued to publish at the highest level [throughout his career]...with over 300 peer-reviewed publications." Wade also credited Baylin's work as one of the reasons that epigenetics is such an important part of cancer research today.

Baylin began his talk by assuring the audience that gratuitously." At the center of the epigenetic cancer model is the phenomenon of abnormally prolonged survival responses at the cellular level to such environmental factors as the chronic stresses of aging, acute inflammation and its products, reactive oxygen species, and chronic injury. These prolonged survival responses can trigger the cascade of biological events that lead ultimately to tumorigenesis.

Epigenetics, according the most widely accepted definition, is the study of sustained heritable alterations in gene expression that are based on factors other than changes in the DNA sequence. While this is a normal process, sometimes the process goes awry, presumably through environmental exposures, and can lead to histone modifications and altered chromatin status. These epigenetic events beget other epigenetic events throughout the multiple layers of memory in the epigenome.

Cancer-related epigenetic changes in gene structure and function can result in the inactivation of genes that otherwise should remain active. Aberrant silencing of genes important to the initiation and progression of tumors affects several groups of genes. These include tumor suppressor genes, developmental transcription factors, tissue remodeling genes, DNA repair genes, cell cycle control genes, anti-apoptotic genes and genes that prevent abnormal activity of developmental pathways in tumors.

Understanding the environmental-epigenetic interface holds promise for translational applications to target metabolic processes in the development and progression of cancer. "One of the important things about research into the environment and epigenetics," Baylin maintained, "is that many of the things we're learning here are turning up biomarkers for the earliest stages of not just cancer, but also other diseases, where epigenetic changes are underlying predisposition or risk. I think they are really going to emerge as markers for prevention."

According to Baylin, the loss of function of genes in tumors, triggering abnormal cellular memory, may be more significantly impacted by epigenetic causes than genetic ones. Epigenetic alterations, in fact, may have pivotal involvement in abnormal clonal expansion of stem and progenitor cells and predisposition to cancer.

"Altered DNA methylation occurs throughout the [cancer progression] process," Baylin maintained, "...and these changes, the genetic and the epigenetic, start very early in the process and can manifest by the time there are the earliest, pre-invasive changes along this progression cascade." It is at this point that Baylin sees the involvement of the environment in pre-disposition and where he hopes to identify potential targets for preventive interventions.

In his review of findings by his group and others, Baylin observed that knowledge of the cancer epigenome is advancing rapidly and progress has been made in identifying a group of target genes common to several cancers. However, he cautioned that much remains to be discovered about basic chromatin function, the relationships of adult stem and precursor cells to normal cell renewal, and the origins and progression of human cancers.

Baylin has received a host of accolades for his work, including appointment to the Virginia and D.K. Ludwig Chair in Cancer Research at Johns Hopkins. Among many other honors and appointments during his career, he received the 2004 National Investigator of the Year Award from the NCI Specialized Program of Research Excellence and the 2005 Shubitz Cancer Research Prize from the University of Chicago.

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