What is it with methylation, anyway? Why does this word keep popping
up in some of the Brady’s most exciting research? Chemically speaking,
methylation is like taking a zipper and adding an extra tooth, so it doesn’t
work properly — or changing the tumblers on a lock ever so slightly,
so the key doesn’t fit it anymore. What does this have to do with
Quite a lot, says William G. Nelson, M.D.,Ph.D., professor of oncology,
medicine,pathology, pharmacology and molecular sciences, and urology.
When a gene is methylated, it’s silenced, rendered useless. In more
than 90 percent of men with prostate cancer, Nelson has discovered, themajor
gene that’s supposed to defend the
|Methylation is like taking
a zipper and adding an extra tooth,so it doesn’t work properly.What
does this have to do withprostate cancer?
prostate against oxidative damage to DNA— incremental harm that
occurs over years or even decades, as carcinogens repeatedly attack our
genes — is silenced, or methylated, early on. This gene is called
GSTPI (pronounced “GST pie”), and what happens here
— this targeted “hit,” an assassination on the genetic
level — allows cancer to develop much more easily.
Exploring the role of methylation as a cause of prostate cancer has helped
Nelson and colleagues look for new genetic markers to help detect it.
Nelson is working to develop tests that can detect abnormal GSTPI
methylation changes in DNA from cancer cells; specifically, the tests
look for altered clumps of DNA, called “hypermethylated CpG islands,”
that aren’t supposed to be there. “Exactly how such tests
might be used has not been established yet,” says Nelson. But, he
speculates, “they could be used in prostate biopsies or even urine
specimens, to help identify men who harbor prostate cancers that have
been missed by prostate biopsy.”Also, such tests targeting CpG islands
of other genes, such as the endothelin B receptor or cyclooxygenase-2
(COX-2), in DNA in prostate cancer cells and tissues, might one
day help doctors predict outcomes from radical prostatectomy or radiation
Methylation and inflammation:
Methylation helps cause cancer. Now, can we somehow backtrack —
retrace the steps of cancer— and catch methylation in the act? Pathologist
Angelo De Marzo, M.D., Ph.D., has been named the Dr. and Mrs. Peter S.
Bing scholar from The Patrick C. Walsh Prostate Cancer Research Fund.
He believes that prostate cancer is driven by a bad combination of forces
from within and without. From inside the prostate comes inflammation;
from without come attacks by cancer-causing elements in the diet. Together,
they causedamage that results in regions of “proliferative inflammatory
atrophy,” or PIA.
De Marzo believes these PIA spots, or lesions, represent evidence of
a “field effect” change, “indicating that a very large
region of the prostate has been exposed to something that causes cancer,”
and that these PIA lesions somehow pave the way for cancer. It may be
that the next step a pathologist could detect in the tissue is high-grade
PIN(prostatic intraepithelial neoplasia), and from there, the next step
To prove that PIA lesions are early precursors on the way towards cancer,
De Marzo is looking for intermediate changes in the DNA between normal
cells and cancer cells. The most common of these changes, which he expects
to find in abundance, is our old friend — the hypermethylated “CpG
island”in GSTPI. “We suspect that PIA will contain
intermediate levels of CpG island methylation, greater than normal, but
less than high grade PIN and carcinoma,” he says. He will also look
for some of the other genes with DNA methylation changes that Bill Nelson
and colleagues have discovered. If his work is able to connect the dots
from PIA to PIN to cancer, he hopes to use these results as pilot data
for a larger, externally funded grant to investigate the order of events
in early prostate cancer.
Better biomarkers to predict recurrence:
Oncologist Joshi Alumkal has been named the Irene and Bernard L. Schwartz
scholar from The Patrick C. Walsh Prostate Cancer Research Fund. He is
studying methylationin a different gene, with the alphabet-soup name of
NKX3.1. Although the genetic players are different, the basic
script is the same: Whatever causes the DNA to methylate in this gene
— or, as Alumkal believes, several genes — knocks out the
body’s ability to prevent cancer’s development, growth, and
spread. In this case, the kind of cancer that results is particularly
unpleasant, and most likely to defy treatment.
The gene NKX3.1 is important in normal prostate development,
and its loss can mean not only that prostate cancer develops, but that
it’s an aggressive form. “Loss of this gene in animal models
leads to precancerous and cancerous prostates — many of which appear
very primitive, much like high Gleason score tumors,” Alumkal explains.
In this case, figuring out a way to screen for these DNA methylation changes
“may help us identify those at highest risk of recurrent and potentially
lethal prostate cancer.”