Hopkins And International Team Maps First Major Cancer Gene To X Chromosome

September 29, 1998

Johns Hopkins researchers, collaborating with an international team of geneticists, have pinpointed the site of the first gene for a major cancer located on the human X chromosome. The gene, for prostate cancer, may account for almost 20 percent of disease in families with a strong history of the cancer, the researchers say. It's the second prostate cancer susceptibility gene this group has mapped, and the first on the X chromosome, which men inherit from their mothers.

"This is clearly a major step toward understanding the factors that lead to prostate cancer," says Hopkins Urologist-in-Chief, Patrick C. Walsh, M.D., one of the study's authors. "We're still at the early stages in figuring out genetic involvement in prostate cancer, but this finding is real progress," says Hopkins geneticist, William Isaacs, Ph.D., a co-director of the study.

The research, reported in the October Nature Genetics, describes the new gene locus, called HPCX (for human prostate cancer on the X chromosome) as responsible for 15 to 20 percent of inherited forms of the diseases. Of the approximately 200,000 new cases diagnosed in the U.S. each year, an estimated 10 percent are inherited.

The study confirms researchers' long-held suspicion that the X chromosome might be important in prostate cancer. Since the 1960s, they have noted that a man's risk of prostate cancer tends to be higher if his brother has prostate cancer than if his father has the disease. That inheritance pattern characterizes genetic traits carried on the X chromosome and passed from mothers to sons, such as muscular dystrophy or hemophilia. The plausible explanation is that a prostate cancer susceptibility gene lies on the X chromosome.

"Mapping HPCX brings us one step closer to understanding the origins of prostate cancer, at least in some families," says Francis Collins, M.D., director of the National Human Genome Research Institute and an author from the NIH team that co-led the study.

"This finding points out once again, the importance of facilitating multi-national collaborative efforts to address a complex disease like cancer, particularly prostate cancer, which is one of the hardest cancers to analyze from the standpoint of a geneticist," says Jeffrey Trent, Ph.D., of the National Human Genome Research Institute and project co-director.

In hunting for genes in disorders where more than one gene plays a role -- probably most major illnesses such as heart disease and schizophrenia -- researchers typically focus on a small population where many family members have the disorder. Or better, as in the case of the breast cancer genes, they look for such families where affected members also have other characteristics, says Isaacs. So, with the BRCA1 gene for breast cancer, for example, it was most easily spotted in those with an early onset age for breast cancer and a family breast cancer history and a high incidence of ovarian cancer.

But with prostate cancer, says Isaacs, "no homogeneous group with such clear characteristics has popped up." In studying nearly 1,000 people with earlier-than-usual onset of the disease and a strong family history of prostate cancer, the researchers found a specific area on the X chromosome that was shared more frequently than one would predict as determined by statistical analysis. That area encompasses the susceptibility gene. Isolating that precise gene is the next step for the researchers. Then, with more study, they'll know whether diagnostic tests should be done and, ultimately, how to design preventive therapies.

"Finding genes for prostate cancer is particularly difficult,"says Isaacs, because it's hard to separate populations of people who get the disease due to a strong-acting mutant gene from those who have it from other causes such as, say, interactions between the environment and less influential genes. "You can have one family where four brothers have prostate cancer but only three have the HPCX gene."

In 1996, the same research team identified the location of the first specific gene that predisposes men to develop prostate cancer. The team named that gene HPCI (hereditary prostate cancer 1) and located in on a region of chromosome 1, one of 22 pairs of non-sex human chromosomes.

Other collaborators on the study were Diha Freije, Sarah Isaacs, Kathy Wiley, Deborah Nusskern, Charles Ewing, Eric Wilkens, Piroska Bujnovszky, G. Steven Bova, of Johns Hopkins; Jeffrey Smith, Joan Bailey-Wilson, John Carpten, Dietrich Stephan, Elizabeth Gillanders, Isaac Amundson, Tommi Kainu, Diana Freas-Lutz Anne Van Aucken, Raman Sood, Bichael Brownstein and Jeffrey Trent, of the National Human Genome Research Institute, NIH; Jianfeng Xu, Deborah Meyers, of the University of Maryland at Baltimore; Agnes Baffoe-Bonnie, of the Fox Chase Cancer Center, Philadelphia; Rebecca Berry, Daniel Schaid, Amy French, Shannon McDonnell, Jennifer Schroeder, Michael Blute and Stephen Thibodeau, of the Mayo Clinic in Rochester, MN., as well as researchers from the University of Tampere in Finland and Umea University in Sweden.

Research was funded by the NIH, The Fund for Research and Progress in Urology at the Johns Hopkins University, and grants from the two universities in Finland and Sweden.
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