After a decade of scrutinizing family trees and DNA, a multi-institutional team has discovered a genetic mutation linked to prostate cancer. Preliminary evidence marks the mutations in the once obscure RNASEL gene on chromosome 1 as responsible for just a tiny percentage of all cases of prostate cancer. However, some tantalizing data suggest that these cases may be among the most aggressive.
"The individuals who carry the mutations seem to present with cancer that leads to poor outcomes," said John Carpten, Ph.D., of the National Human Genome Research Institute, Bethesda, Md. As lead author on a research letter in this months Nature Genetics, Carpten reported two mutations in RNASEL, each from a different family with an overwhelming history of prostate cancer.
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In the first family, four brothers carried the same mutationa base substitutionin RNASEL. Three of the men presented with advanced cases of prostate cancerGleason scores of 7 and above with evidence of disseminated disease. The fourth brother also had prostate cancer, but his diagnostic data were not available.
The second family, who were African-American, harbored a different mutation but faced a similar situation. All six brothers developed prostate cancer, with the average age at diagnosis a relatively young 59. Four of the six men carried this mutation, also a base substitution in RNASEL, with three of the men displaying aggressive disease. The other two cases were apparently unrelated to RNASEL.
"Prostate cancer is such a common disease that, in any family, there could be a number of sporadic cases," said Carpten. "This is especially true in African-American families because they are two times more likely to develop the disease."
All of the early evidence pointed to RNASEL acting as a tumor suppressor. Men inherit one mutated allele and one normal allele. At some point, a random sporadic mutation knocks out the normal copy, leading to a complete loss of function of the gene.
Until its recent connection to hereditary prostate cancer, RNASEL had been languishing in genomic backwaters. Fortunately, a team at the Cleveland Clinic Foundation had been studying RNASEL to discern its role in the bodys antiviral response. In a 1999 review paper, Bryan R. G. Williams, Ph.D., of the Lerner Research Institute at the Cleveland Clinic Foundation, wrote that the genes product, a tyrosine kinase, signals cells to churn out inflammatory factors.
If this were all the gene did, its role in prostate cancer would remain a mystery. But it apparently plays a second, related function: acting as a trigger for apoptosis. "In the presence of viral pathogens, the double-stranded DNA from those viruses would be degraded by RNase L [the term for the protein]," said Carpten. "But it may have a broader role in apoptosis."
According to this idea, when men lose both RNASEL alleles, their cells also lose the ability to break down RNA, whose degradation triggers apoptosis. These errant cells survive and gain a growth advantage, which can lead to other types of cancer.
Carpten speculated that the apoptosis signaling pathway involving RNASEL may be particularly responsive to androgen. If true, that theory would explain why the gene leads to prostate cancer but apparently not to other types, even though it is expressed in the testis, uterus, intestines, and elsewhere.
Three Streams
The discovery of the mutation arrives downstream from the confluence of three disparate research streams: the intense genetic analyses at the National Human Genome Research Institute; the characterization of RNase L at the Cleveland Clinic; and large family linkage studies at Johns Hopkins Medical Institutions, Baltimore.
As far back as 1960, epidemiologists have had an inkling that prostate cancer could, in some cases, be hereditary. In the 1980s, it became obvious to Hopkins urologist-in-chief, Patrick C. Walsh, M.D., that it indeed was. Throughout his career as a pioneering prostate surgeon, Walsh routinely saw fathers, sons, and brothers with prostate cancer. He directed his department to initiate a widespread search for hereditary influences.
Eventually, Walsh and Hopkins behavioral scientist Sally Isaacs, Ph.D., screened some 2,500 families that met the criteria for hereditary prostate cancera real phenomenon borne out by their earlier epidemiology. The scientists selected 79 families hardest hit by prostate cancer and gathered blood samples.
With colleagues at National Human Genome Research Institute, Hopkins William Isaacs, Ph.D., applied ever more sophisticated statistical tools while sifting for patterns of inheritance. By 1996, the team had picked a region on chromosome 1 as the leading candidate for a prostate cancer gene. Even so, the task ahead loomed enormous. "Its like trying to pinpoint a certain restaurant in Hong Kong and your first stepidentifying the continent of Asialeaves a lot of work," Williams wrote in his urology departments newsletter. Much of that genomic triangulation occurred at NHGRI, under the direction of Jeffrey Trent, Ph.D.
With RNASEL in hand, the team is now turning its tools to another gene with strong links to prostate cancer. The same painstaking work that turned up RNASEL has identified a promising stretch along the X chromosome. There is a good chance, Carpten said, that, along with RNASEL, this gene will in the end turn out to be just one of many related to prostate cancer.
"It could be a major player, it could be a minor player," said Carpten. "It could be a major player in certain populations. All of that work needs to be done."
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