Breast, colon and prostate cancers share one typical characteristic. Like many other malignancies, they come in two persuasions: familial and sporadic, which is to say, inherited or acquired by chance.
Prostate cancer (PC) is the most common malignancy in American men. Its No. 1 risk factor is advancing age; 80 percent of all PCs occur in patients over 65 years old. In 2001, doctors diagnosed 198,100 new cases of PC, and 31,500 men died of the disease. Where a father or brother in a family has had prostate cancer, risk goes up twofold. “Only 9 percent of all prostate cancer cases are inherited,” observed molecular biologist Katherine Klinger, “but they cause 40 percent of the cases diagnosed before age 55.”
Klinger is senior vice president of research and development at Genzyme Molecular Oncology in Framingham, Mass. She is a key co-author of a paper in Nature Genetics for February 2002, just released online. The article’s title: “Germline mutations in the ribonuclease L [RNASE L] gene in families showing linkage with HPC1 [Human Prostate Cancer chromosomal region].” Its senior author is cancer geneticist Jeffrey Trent, scientific director of the National Human Genome Research Institute in Bethesda, Md.
“RNASE L appears to be the gene that accounts for a proportion of the inherited cases of prostate cancer,” Klinger told BioWorld Today. “It took a long time to discover, and required participation of a lot of people with different acquired skill sets and resources.” She was referring to the 41 co-authors at 14 institutions. They were marshaled by Trent into a consortium to hunt prostate cancer genes.
“When you find a gene,” Klinger continued, “a lot of times you say, Gee, I wish I knew what it did.’ But in the case of RNASE L, we have a pretty good understanding of its main role. It functions as a major regulator of cell proliferation and apoptosis. Right away we could get a feeling for what was going on in terms of the biochemistry and biology of inherited regulated prostate cancers. It’s supposedly a tumor suppressor gene a potentially druggable target.”
RNASE L Gene: Elusive But Major
“A number of different genes have been mapped on chromosomes 17, 20 and X,” Klinger recalled, “for various proportions of inherited prostate cancer. This particular one, RNASE L, on the long arm of chromosome 1, is felt to be one of the major loci, though elusive.
“The work was started in 1992,” she recounted, “and the first mapping of chromosome 1 reported in 1996. Then in late ’97 or ’98, Trent approached us, because Genzyme Molecular Oncology had developed a technology that was very efficient at scanning large regions of DNA, looking for genes. He invited us to collaborate with their consortium, which we have done now for a number of years.
“The first phase,” Klinger recounted, “was collecting all the families and doing the initial mapping. Then the middle phase, where we were sorting through the genes and saying: Is this it? No, it’s not.’ And finally, the latest gene-finding phase.
“This positional cloning work has spanned probably a decade or more,” she observed, “and you can imagine that the technology has expanded in that time. The process began when we all said we believe there is an inherited trait. So Trent and his co-authors started collecting families that seemed to fit that criterion multiple affected members, onset before age 55, very severe tumor grade. From these individuals we established lymphoblastoid cell lines to have enough material to study. Then we started working through all these polymorphic markers, asking does the disease gene segregate in families with this marker or not. Ultimately it narrowed down to a region on chromosome 1 of maybe 10 megabases to begin with.
“Then they collected more families, to try to refine that mapping and make the critical interval smaller. So when that got down to a megabase or two, that’s when we started applying this gene-recovery scanning. That’s where we came in with exon trapping, to identify the genes. Toward the end of this process, the Human Genome Project sequences became available. With their help, we could do computer predictions, saying: What gene should live in here?’ And when we asked if that gene is a candidate for prostate cancer inheritance, the RNASE L gene popped up.
“So far, only a small number of mutations have been looked at,” Klinger observed. “They were found in two of eight families with linkage to the hereditary type 1 prostate cancer. Any time you think of a disease like colon cancer or prostate cancer or breast cancer, where there’s a very high incidence of sporadic, noninherited cases in the population, as well as the less common inherited form, you’d have to worry that you’re clearly looking in a family whose members have inherited the gene not got it by chance.”
Genzyme Molecular Oncology has acquired the exclusive license to the newfound prostate cancer gene.
For Drug Design, An Interesting Target
“It’s certainly going to be an interesting target for drug designing from a biochemical or biological point of view,” Klinger pointed out. “We’re thinking about a small-molecule or a gene discovery approach, and how to formulate a high-throughput screen. From what that screen showed, we’re hypothesizing a couple of clinically important diagnostic or therapeutic compounds. But there are still two questions that need to be answered first:
“How frequent is the real incidence of this gene? What percentage of inherited prostate cancer does it account for? That work is ongoing for determining real mutation frequency. Second: Do these gene mutations play any role in the noninherited form of prostate cancer?
“If you look at retinoblastoma,” Klinger explained, “there is an inherited form of that disease and a sporadic form. But mutations in the same genes play a role in both forms. So in families you know are at high risk, you obviously want to provide therapy. The frequency of the mutations is what we need to know. If that were to play a role in some proportion of what we recognize as sporadic, not inherited,” she concluded, “that’s another segment of patients that could be reached.”