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.
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