New Genes Found, New Questions about What Causes Prostate Cancer
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.
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 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."