In the highest-mortality ailments of all, the riskiest risk factor is advancing old age.

Heart attacks and cerebral strokes strike most of their victims in the 50s and up. Prostate cancer also afflicts men in their elderly and later years. The two diseases apparently have nothing in common beyond encroaching life spans.

Yet this week's Nature Genetics online release, dated Sept. 16, 2002, bears the title: "Germline mutations and sequence variants of the macrophage scavenger receptor 1 gene [MSR1] are associated with prostate cancer risk." The article's senior author is molecular biologist William Isaacs, professor of urology and oncology at the Kimmel Cancer Center at Johns Hopkins University in Baltimore. Its co-senior author is human genomicist Deborah Mayer, at Wake Forest University School of Medicine in Winston-Salem, N.C.

"This is the first time that the MSR1 gene has been linked to cancer," Isaacs told BioWorld Today, "and it may tie infections and similar environmental exposures to cancer of the prostate in a way that we haven't thought about before. First of all," he continued, "we don't know of any direct link between heart disease and prostate cancer. But this gene had been quite extensively studied in the context of atherosclerosis and low-density lipoprotein [LDL] - the bad' cholesterol. Also, LDL's receptor, and another receptor, which didn't take up native LDL but bound to modified LDL. This modified LDL receptor turned out to be that MSR1 gene. So if you had a lot of LDL in your high-fat diet, macrophages would become lipid-laden, and turn on these foam cells, which are characteristically found in atherosclerotic plaques.

"We've been studying prostate cancer [PC] and its genetics for about 10 years," Isaacs went on, "particularly focusing on macrophages. More recently, on case-controlled studies to identify gene variants that may be more common in the general population of prostate cancers, compared to men who do not have the disease. In the course of our studies, we've identified these mutations in this MSR1 gene, which resides on chromosome 8. And we think they're associated with an increased risk of PC in African-American men as well as men of European descent or the Caucasian U.S. population."

Is Immune System's Macrophage PC Miscreant?

"We think it's a very interesting study population that we've examined," Isaacs continued, "but additional studies will need to be done to test the generalizableness, or reproducibility, of these results. What we are excited about is finding mutations in this particular gene. MSR1 has a low a priori likelihood of being a prostate cancer susceptibility gene, in the sense that it's really a macrophage-specific gene. We think it's expressed only in macrophages, and as such we think that finding mutations in this gene implicates macrophages as important determinants of risk for PC."

The co-authors screened a total of 1,663 men in families including 764 members with hereditary prostate cancer (HPC). As Isaacs recounted, these cohorts included three populations: "The first co-authors did the first sequencing on MSR1 in our HPC families' probands. They were the first to observe these mutations in these family members. The second population we looked at," he continued, "was in a group of men with PC, who may or may not have a family history. The frequency of these mutations that we had observed in the hereditary families was assessed in these men, and compared to the frequency in those we thought did not have PC.

"That's where the statistical significance of our findings arises," Isaacs pointed out. "For example, this inactivating mutation that we found in the MSR1 gene is about six times more common in men with PC than in men without it. Hence, the defect is associated with an increased risk of PC.

"Our third population was an attempt to look at a different cohort of men. These we knew PSA [prostate-specific antigen] values on, but we didn't know anything about their PC status per se. They were all originally ascertained by virtue of a study that was completely independent of PC. It was set up to study the effects of asbestos exposure at random. The prostate cancer rate we saw in these 518 men was no different from what you see in the general population.

"So we thought this was a surrogate for a general population, with a large number of men, of which subsequently we did know the PC status. So in this group, too, mutations were found at a frequency intermediate between a population where everybody has PC within a population where we think nobody has PC. And in that asbestos group, several of the mutation carriers turned out in fact to have prostate cancer. This supported the idea that these gene mutations may increase the risk of PC development."

Gene Defects No Respecter Of Ethnicities

"Within those three groups," Isaacs added, "we compared African-American men who had PC to African-American men without it. We were interested to see that in men of European descent, or Caucasian men or white men, basically from the U.S., as well as African-Americans, these variants appeared to increase the risk of PC."

Isaacs pointed out that "another prostate cancer risk factor is oxidative stress [OS] related to inflammation. OS has been implicated in many disease processes, and also normal aging. We know that oxidative damage to DNA can be a quite potent mutagen. We think that it may play a very important role in PC, because the best-known preventive for PC involves antioxidants. So the increased consumption of lycopene, selenium or vitamin E may be due to their ability to reduce oxidative stress. And a high-fat diet may perhaps be acting as a risk factor for PC by increasing OS.

"We think that one implication of our work," he summed up, "is that macrophage biology may be more important than previously thought as a component of prostate carcinogenesis. Once we know more about what the mechanism is, an intervention strategy aimed at macrophages may be of interest in determining risk of prostate cancer.

"While we are confident of the results we presented," Isaacs concluded, "we also know that prostate cancer is a heterogeneous disease, and these studies need to be replicated in other populations in order to be significant."