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You’re a policeman, looking for a serial killer.
You scrutinize clues, interview countless witnesses, examine DNA
and crime scenes, and gradually a pattern of behavior emerges.
You can make certain predictions about where he’ll appear. You
develop a profile of the criminal, and eventually, a description
that’s good enough for a police artist to draw the suspect. Then,
after months or years of hard work, you strike gold—a DNA match
that’s good enough for you to make an arrest. Will it stick?
This is something like the life and career of Bill
Isaacs, Ph.D., except he’s been on this particular search for
the last decade, and he’s sifted through tens of thousands of
clues. Isaacs is the William Thomas Gerrard, Mario Anthony Duhon,
and Jennifer and John Chalsty Professor of Urology. The killer
he’s looking for is inherited prostate cancer, which runs in families,
and strikes men at a younger age. Using a technique called linkage
analysis, Isaacs has scrutinized blood samples from hard-hit prostate
cancer families, looking for subtle irregularities. He had narrowed
down his focus considerably, targeting suspicious areas on chromosomes
1, 8, and the X chromosome. Now he and colleagues at Hopkins,
Wake Forest University and the National Human Genome Research
Institute, have gone a step farther, and identified likely suspects—
two candidate genes.
One of them, on Chromosome 1, called RNASEL, is
the candidate for what Isaacs and colleagues have been calling
HPC1 (the first hereditary prostate cancer gene), for the last
six years. When a cell goes bad—when it develops a mutation, or
otherwise becomes sick—it is supposed to self-destruct. Nature
has a mechanism for this, called the “suicide” (or apoptosis)
pathway. RNASEL, it turns out, is part of this. “RNASEL usually
sits in most cells in an inactive form,” says Isaacs. “When it’s
activated, it cuts RNA, and causes the cell to die.” Why is this
important? RNA, ribonucleic acid, is the “working copy” of DNA,
used in bulk quantities by each cell. The body has only two copies
of DNA— one from each parent—but thousands of copies of RNA. If
DNA is the master plan of a house, RNA would the blueprints used
by the builders. If there is a bad copy of the plan, it could
be disastrous for the house if all defective copies were not immediately
destroyed.
“This is what is supposed to happen when the cell
becomes stressed or damaged and can’t repair itself,” says Isaacs,
“instead of surviving in a mutated form, which may set the stage
for the development of cancer. It’s better to have the cell die
than to survive with damaged DNA. But cells that don’t have RNASEL
don’t die when they should.
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| Scientists
have long wondered whether a virus or other “outside influence”
could have anything to do with prostate cancer. “With the
inflammatory aspects that we have seen in the early development
of prostate cancer, it may be that infection early in life
sets up the disease.” |
Isaacs’ work dovetails
with the research of Angelo DeMarzo and Bill Nelson on oxidative
damage to the prostate. Oxidative damage is incremental, injury
caused over many years, as free radicals (a toxic byproduct of
everyday metabolism) attack the DNA in cells, causing mutations
that lead to cancer. Nelson’s pioneering work has shown that diet
plays a key role in oxidative damage to the prostate; DeMarzo
has shown that this damage is preceded by inflammation, which
Nelson and others, in turn, have shown to be preceded by the knockout
of a gene called GST-p. “Fortunately, RNASEL is a gene that was
well characterized about 20 years ago, as an interferon-inducible
gene.” Interferon was heavily investigated in the 1980s as an
anti-viral agent, and also as an anti-cancer agent. “One of the
reasons we think it may have some anti-cancer activity is that
interferon activates this pathway, and promotes cell death, which
would block formation of the cancer.” Until now, no one has ever
linked RNASEL to prostate cancer.
Isaacs and colleagues
are also intrigued by the idea that the gene may have antiviral
effects. Scientists have long wondered whether a virus or other
“outside influence” could have anything to do with prostate cancer.
“With the inflammatory aspects that we have seen in the early
development of prostate cancer, it may be that infection early
in life sets up the disease,” suggests Isaacs. “We don’t know
yet.”
The investigators
found mutated RNASEL genes in two of a group of 79 prostate cancer
families. “In one family, there are five brothers; four have prostate
cancer, and all four have the mutated RNASEL gene,” Isaacs says.
“In another family, there are six brothers, all of them have prostate
cancer, and four of the six carry the inactivated RNASEL gene;
two don’t. Our assumption is that the other two men got prostate
cancer as a result of the many other reasons why people get prostate
cancer.” Isaacs is a bit dissatisfied with the low, although striking,
numbers; he thinks the linkage to chromosome 1 should account
for a larger fraction of the families. Thus, he and colleagues
are looking for additional mutations in RNASEL, and continuing
the search for other mutated genes in the same neighborhood.
An
“Unexpected” Gene
The other newly discovered candidate is an “unexpected” gene—here,
too, a gene that has been studied intensively in connection with
something else: Heart disease. This discovery, by scientists from
the Wake Forest University School of Medicine, the Brady Urological
Institute and the Kimmel Cancer Center at Johns Hopkins, the National
Human Genome Research Institute, and St. Louis University, was
published in Nature Genetics.
The gene, called MSR-1,
for “macrophage scavenger receptor,” is located in another neck
of the genetic woods, on the short arm of chromosome 8—an area
long suspected by Isaacs and colleagues to contain one or more
prostate cancer susceptibility genes. “We knew the area was a
fertile hunting ground,” says Isaacs. “What we didn’t expect was
that macrophages may turn out to play a role in prostate cancer.”
Normally, the MSR-1
gene functions as a cellular vacuum cleaner, absorbing debris
like a napkin soaks up grease—sponging damaged lipids in heart
disease, and bacterial pathogens in areas of infection. It had
not previously been thought of in connection with cancer because
it does not control cell division. Genes believed to cause cancer
are usually involved in cell birth or death.
The researchers zeroed
in on the MSR-1 gene by scrutinizing blood samples from 159 prostate
cancer families at Hopkins and elsewhere. In these families, they
found eight different mutations in the gene, none of which had
ever before been described in any of the large genomic data bases.
In some families, there was a “missense” mutation, in which one
amino acid is exchanged for another in the MSR-1 protein, presumably
decreasing its function; and in other families there was a “nonsense”
mutation, clearly leading to a complete inactivation of the gene.
Once they determined
that these mutations occurred in hereditary prostate cancer families,
the scientists looked for changes in the MSR-1 gene in hundreds
of men with and without prostate cancer. The 365 men with prostate
cancer—335 were patients at Hopkins, and 30 were part of a study
at Wake Forest—did not have the hereditary form; instead, they
had the “sporadic” cancer that just happens over the course of
a lifetime, probably due to a combination of environment and genetics.
The 366 unaffected men were recruited among men participating
in screening programs for prostate cancer.
The scientists noticed
a clear difference in the MSR-1 gene mutations in the men with
prostate cancer and the men without. In men of European descent,
MSR-1 mutations were found in 4.4 percent of men with prostate
cancer, but in hardly any—0.8 percent—men without cancer. MSR-1
mutations were found in 12.5 percent of African American men with
prostate cancer, but in a very low percentage —1.8 percent—of
African American men without cancer. “This genetic evidence suggests
that MSR-1 may play an important role in prostate cancer susceptibility
in both African American men and men of European descent,” says
Jianfeng Xu, Ph.D., of the Center for Human Genomics at Wake Forest.
Macrophages are part
of the immune system’s arsenal; they are present in allergic reactions,
and in inflammation. “The MSR-1 gene is thought to help in the
formation of atherosclerotic plaques,” says Isaacs. Laboratory
mice missing the MSR- 1 gene are less likely to develop heart
disease. Another macrophage job is to help the body fight off
infection. Laboratory animals that don’t have MSR-1—in addition
to having less heart disease—are more susceptible to infections.
Macrophages are normally
found in the prostate, and in the very subtle inflammation that
appears just before cancer develops. “The implications are actually
quite staggering,” Isaacs says. “We think there’s some important
role that the macrophage plays in prostate cancer—either in promoting
it, or preventing it. We think it’s inactivated, that it’s a lack
of macrophage function that allows the prostate cancer to occur
in these families —and that normal macrophage function is required
to prevent prostate cancer.”
Whether the MSR1 gene’s
role in prostate cancer is related to that of RNASEL—or whether
they act separately, ending with the same result out of coincidence
—is not yet clear. “A lot of the things we’re doing point to the
same types of issues—oxidation, perhaps due to inflammation, or
perhaps infection, along with diet,” says Isaacs. “This idea that
there are some outside factors important in prostate cancer, and
identifying what those are, could be really critical. Now it’s
up to us to figure out if they’re important, how they’re important,
and how we can use this information to more effectively manage
or even prevent prostate cancer.”
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