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Epigenetics and Prostate Cancer: The Next
Big Thing in the Unraveling of Prostate Cancer Biology
(October 2006)
This
article isn't an exposition of the molecular biology of epigenetics,
e.g. promoter methylation, chromatin restructuring from histone
modifications, histone deacetylase inhibitors, etc. But rather it is a
concise alert to clinicians that developments in the understanding of
the epigenetics of prostate cancer are beginning to provide insight into
the inception and progression of the disease, improve estimates
regarding prognosis, and, in the future, lead to new treatments.
"Epigenetics"
refers to the study of heritable changes - acquired or inherited - in gene
_expression independent of changes in the DNA sequence. Epigenetic
(literally "above the genome") molecular mechanisms controlling gene
expression are especially significant in the biology of cancer, involving
"silencing" of tumor suppressors, and releasing undesirable constraints on
the transcription, e.g. by unleashing restraints on cell-cycle regulators
resulting in excessive proliferation. Throughout the course of the
disease, from its inception through progression to androgen independent
metastatic disease prostate cancer displays increasing disruption of
normal gene expression, especially resulting from aberrant methylation of
gene promoter sequences. These alterations can be detected and quantified
in core biopsy specimens, in the cellular sediments in urine, and in
extra-cellular tumor DNA in peripheral blood plasma and serum.
The many
snippets of epigenetic research peppering the current literature were
joined in the comprehensive review, "The emerging roles of DNA methylation
in the clinical management of prostate cancer" in Endocrine-Related Cancer
(2006)13 by Perry et al. The article's lead sentence reads: "Prostate
cancer has a unique set of problems with its early detection, diagnosis
and treatment that might be aided by the complementary use of molecular
markers such as DNA hypermethylation".
What are
some of these areas where quantification of the DNA methylation status
could be informative?
1) In diagnosis: by employing a panel of methylation
markers for early detection. The putative progression of HGPIN to PCa is
marked e.g. by increasing methylation of the GSTP1 gene (coding for a
detoxification enzyme), for which a urine and serum test is in current
clinical use. Also, "A four-gene panel of GSPT1, APC, PTGS2 and MDR1 [can]
distinguish primary CaP from benign prostate tissue with 92% specificity
and a sensitivity approaching 100%".
2) By utilizing promoter hypermethylation as a
prognostic indicator for prostate cancer: "Several studies have now shown
that the 'methylation index', defined as the ratio of methylated genes to
the total number of genes analyzed, correlates with the clinicopathologic
indicators of poor prognosis". Patterns of gene methylation -veritable "methylation
signatures" are becoming associated with advancing pathologic stage and
grade.
3) By
identifying the silencing of genes that suppress metastases: methylation
of genes for E-cadherin and CD44, both of which promote cell-cell
adhesion, may serve as an alert to metastatic potential.
"DNA
methylation alterations affects at least 30 genes. ...[and] These changes
make prostate carcinoma particularly susceptible to drugs targeting
chromatin and DNA modifications" (Schultz,'Epigenetics of prostate cancer:
beyond methylation', J.Cell.Mol.Med., Oct.,2006). Since epigenetic
alterations are potentially reversible, drugs to reverse the
effects of unwanted methylation are under active development. Two
5-aza-cytidine compounds are in current clinical and protocol usage.
Another class of drugs under investigation, the histone deacetylase (HDAC)
inhibitors, prevent the removal from histone tails of the acetyl groups
that maintain an open passageway for the transcription machinery to access
DNA. "The administration of these drugs causes multiple changes as a
consequence of demethylation, including activation of silenced genes,
decondensation of chromatin and induction of cellular differentiation"
(Perry).
On Friday, November 17th, at Swedish Hospital, the Annual
Roland Pinkham Basic Science Lectureship is focusing on "Epigenetics: One
Step Above the Genome" to promote clinicians' understanding of this
developing science, a science which will likely pervade clinical medicine
in the future. Addresses will discuss the underlying basic science, gene
silencing, environmental and dietary effects on gene _expression,
relevance of epigenetics to cancer, emerging directed therapies, and
epigenetic factors affecting memory and aging. To register go the
www.swedish.org/cme
, or
call 206-386-2755
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