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Complimentary DNA microarrays' role in
the analysis of PC gene expression in search of additional diagnostic
information and therapeutic targets. (February 2003)
With the nearly complete sequencing of the human genome only recently
accomplished, the NEXT BIG THING is already well upon us. That is,
utilizing the new knowledge and the emerging technology to understand how
the genes orchestrate cellular function...and dysfunction. We don't need
to understand the mechanics of cDNA arrays, 2 dimension gel
electrophoreses, protein chips, mass spectroscopy, laser capture
microdissection, etc., but do need to know how to comprehend the direction
of this science and how it will advance diagnostics and identify targets
for therapeutic intervention. This section will present some of the early
findings resulting from the use of complimentary DNA (cDNA) microarrays in
the analysis of gene expression.
Being musically inclined, I like to think about gene function using the
analogy of a piano with its 88 keys - except the genome has 30,000 or so
genes ("keys"). In all cells there is always background "music" playing,
the "basso continuo" so to speak, representing the housekeeping genes for
the basic operation of the cell. Then, I envision a multitude of pianists,
one "playing" in each cell type - a prostate cell pianist, a heart cell
pianist, a breast cell pianist..and so on, each playing the unique "chord"
of gene expression for that cell type (however, he'll need 100, 200, who
knows how many fingers to play the "prostate cell chord"). How the
prostate maestro knows not to play any inappropriate notes from the breast
cell score is still a mystery, now being studied under the heading of
"gene silencing." If the prostate musician plays a chord with all the
correct notes the result is a normally functioning prostate cell. Play a
few clinkers (sour notes resulting, for example, adverse mutations that
might give unwelcome growth advantage); while at the same time missing
some proper keys (perhaps ones that repair damaged DNA) and the result is
a discordant sound. Really mess up, and you have a very malignant cell.
Only modern gene expression technology and bioinfomatics can compute the
complexity of the simultaneous multiple gains and losses of gene
expression suggested by this analogy, and then reduce the candidates to a
useful but manageable number. Important information is beginning to emerge
from this field of science, but we are only at the beginning. The
following are a very few studies selected from the many that resulted from
a literature search on PubMed under the query "Prostate cancer AND gene
expression".
1) 63,175 probes evaluated differences between examples of PC that were
cured by local treatment versus lesions that had metastasized. 3000
tumor-intrinsic genes were identified that were 3X more expressed in PC
vs. normal. They involved functional categories such as cell cycle
regulation, DNA replication, and DNA repair
2) 12,600 gene products were evaluated comparing PC vs. normal. The PC
cell showed 63 products (mRNAs) that were unique to PC and found that the
PC cell lacked 153 normal mRNAs. This study underscored the need to
consider the balance between up- and down-regulation of gene expression.
3) Gene expression compared patterns characteristic of various levels of
PC aggressiveness (ranging from those that remained local vs. metastatic
disease and relating specimens with Gleason sums 4 - 9). 84 genes were
identified that were altered significantly in prostate cancer, and 12 were
found that were only expressed in aggressive PC as opposed to
organ-confined disease.
4) Genes expression differences were sought among 1176 known PC genes to
identify patterns that were associated with progression from androgen
sensitive to androgen insensitive disease. 34 genes were up-regulated and
8 down-regulated in androgen independent cells
The data flowing from studies such as these are of such abundance that
meta-analyses are being conducted to cross validate findings to identify
significant commonalities that would facilitate the manageable use of this
type of data for diagnostic and therapy targeting purposes.
Seattle is an important hub for this type of work. Dr. Leroy Hood's
Institute for Systems Biology (north shore of Lake Union), the Fred
Hutchinson Cancer Research Center, the University of Washington (and in BC
the Prostate Centre at the Vancouver General Hospital) share more than $23
million in grants to study the gene expression patterns of PC focusing on
issues such as why PC spreads preferentially to bone, the gene expression
difference between men who are cured, and those who relapse. Also, a blood
test is being sought to identify these tendencies.
Bottom Line: We're in a new era of scientific advancement with much
to hope for.
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