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EMERGING RESEARCH FRONTS - 2008

Stephen A. Baylin & Peter A. Jones talk with ScienceWatch.com and answers a few questions about this month's Emerging Research Front in the field of Molecular Biology & Genetics.
Baylin Article: The fundamental role of epigenetic events in cancer
Authors: Jones, PA;Baylin, SB
Journal: NAT REV GENET, 3 (6): 415-428 JUN 2002
Addresses: USC, Keck Sch Med, Kenneth Norris Jr Comprehens Canc Ctr, Dept Urol, 1441 Eastlake Ave,MS83021, Los Angeles, CA 90089 USA.
USC, Keck Sch Med, Kenneth Norris Jr Comprehens Canc Ctr, Dept Urol, Los Angeles, CA 90089 USA.
USC, Keck Sch Med, Kenneth Norris Jr Comprehens Canc Ctr, Dept Biochem, Los Angeles, CA 90089 USA.
USC, Keck Sch Med, Kenneth Norris Jr Comprehens Canc Ctr, Dept Mol Biol, Los Angeles, CA 90089 USA.
Johns Hopkins Med Inst, Sidney Kimmel Comprehens Canc Ctr, Dept Oncol, Baltimore, MD 21231 USA.
Johns Hopkins Med Inst, Sidney Kimmel Comprehens Canc Ctr, Dept Med, Baltimore, MD 21231 USA.
(addresses may have been truncated.)

Why do you think your paper is highly cited?

We described the accumulating data obtained over a decade of growing interest in the epigenetic changes in cancer. This evidence showed that abnormal silencing of genes plays a surprisingly major role in the biology of human cancer—from initiation through progression. We summarized what was then known about the molecular components of this silencing and factors such as aging which may cause it.

"Our work makes the study of abnormally DNA methylated and silenced cancer genes an important model for studies of the components epigenetic control of genomic function."

We presented the impact of the growing numbers of genes involved, suggesting that there may be more epigenetic changes than actual mutations which cause loss of gene function in cancer. Finally, we pointed out the tremendous potential of using abnormal gene promoter DNA methylation changes as cancer biomarkers and the possibilities for reversal of abnormal gene silencing as a cancer therapy strategy based on the molecular biology that was emerging.

Does it describe a new discovery, methodology, or synthesis of knowledge?

The review did this in the context that aberrant gene promoter DNA methylation had only been discovered and believed to be important some seven years or so prior to our paper—and the basis of epigenetic therapy relied first on Dr. Jones’ discoveries in the 1980s about the demethylating capabilities of the drug 5-aza-cytidine matched with discovery of the synergistic effects of this drug class, with histone deactylase inhibitors, for re-expressing abnormally DNA methylated and silenced genes.

Would you summarize the significance of your paper in layman's terms?

The paper reviewed the discovery that abnormal DNA methylation of gene start sites in cancers of many types provided a mechanism to abnormally suppress the production of proteins from these genes. The review then stressed that this pathway to loss of gene activity constituted an alternative way for mutations to disrupt proper protein function. Finally, since the primary DNA structure of the affected genes is normal, unlike for mutated genes, reversal of the abnormal DNA methylation at the gene start sites provides a means to readily restore normal function to affected cancer genes.

How did you become involved in this research and were any particular problems encountered along the way?

Dr. Peter Jones started in this field in 1977 when his group observed that 5-aza-analogues of cytidine caused completely unexpected changes in gene expression. Later in 1980, he established the link between demethylation and gene induction. Dr. Stephen Baylin’s involvement began in the mid 1980s when his group serendipitously discovered the above abnormal DNA methylation of the start sites of genes in cancer cells. It was extended by our findings that this process indeed was a common way to produce loss of function of truly important cancer genes in the mid 1990s.

Where do you see your research leading in the future?

Our work makes the study of abnormally DNA methylated and silenced cancer genes an important model for studies of the components epigenetic control of genomic function. This plays into the exploding interest in such epigenetic control in virtually all areas of the biological sciences.

For cancer, our work will be pointed in following the potential, as stated above, in developing abnormal DNA methylation and other components of the attendant gene silencing as cancer biomarkers—and, through understanding the gene silencing at a molecular level, in developing the concept of epigenetic therapy as a prevention and therapeutic strategy for cancer.

To facilitate all of these goals, our groups will be part of efforts to scan the cancer epigenome to chronicle all the genes involved in abnormal epigenetic regulation and to map this epigenome for the DNA methylation and other molecular marks that cause and maintain the gene silencing.

Do you foresee any social or political implications for your research?

The potential benefits of the ongoing research to health, in terms of cancer and other diseases, is very large and the whole field of epigenetics, including the cancer research described in our paper, emphasized the need to markedly increase funding to map epigenomes of humans and other organisms for expanding basic biological knowledge and improving health care. The NIH has recently announced a Human Epigenome Roadmap project.

Stephen B. Baylin, M.D.
Deputy Director
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University
Virginia and DK Ludwig Professor of Oncology
Baltimore, MD, USA

Peter A. Jones, Ph.D., D.Sc.
Director
University of Southern California/Norris Comprehensive Cancer Center
Distinguished Professor of Urology, Biochemistry and Molecular Biology
Los Angeles, CA, USA
 



2008 : April 2008 : Peter A. Jones & Stephen A. Baylin