AT LAST, GENETIC PROOF
Prostate Cancer Can be Inherited
In this genetic detective story, involving 91 families from three countries who have been devastated by prostate cancer, the discovery is like finding the first fingerprints at the scene of the crime.
It has been a painstaking quest, and it's far from over. But there has been a major breakthrough in the search to unravel the secrets of prostate cancer: The first conclusive evidence of a genetic defect that predisposes some men to the disease, and causes prostate cancer to run in some families.
The presence of a familial prostate cancer gene (or genes) has long been suspected; in 1992, Johns Hopkins researchers were the first to establish an undeniable link between a family history of prostate cancer and a man's risk of developing the disease, and to characterize the distinct phenomenon of Hereditary Prostate Cancer (HPC). But until now, no proof has ever been found. In this genetic detective story, involving 91 families from three countries who have been devastated by prostate cancer, the discovery is like finding the first fingerprints at the scene of a crime.
Investigators from the Brady Urological Institute, in collaboration with scientists from the National Human Genome Research Institute and from Umeä University in Sweden, recently reported that they've linked the disease to a gene at a specific location -- a site on chromosome 1. The discovery is not an exact "street address," but it's a promising road sign that shows scientists where to look next and narrows the search considerably, says Patrick C. Walsh, M.D., Urologist-in-Chief, who launched this effort 10 years ago. "This study proves that prostate cancer can be inherited like other cancers -- a fact that many people somewhat doubted. Now we know on which chromosome it's located, and armed with that information, we can go after the gene."
This particular gene is probably responsible for about one-third to half of cases of hereditary prostate cancer -- and only about 10 percent of all cases of prostate cancer are thought to be purely hereditary. But many scientists believe that the defective gene or mechanisms involved in hereditary prostate cancer are the same ones that somehow go askew in "sporadic" cancer, disease that just develops over the course of a lifetime -- the kind most men get. (Most scientists believe that cancer happens because of a combination of "hits" -- at least one genetic aberration, plus one or more things environmental, such as a poor diet, or smoking. Think of a genetic slot machine, in which -- in order to develop a disease -- you need to get two, three, or five oranges in a row; having a bad gene is worth at least one orange.)
The next step is to identify the gene, says Walsh, and the ramifications of this will be immense: "First of all, it will enable us to identify the families that carry this mutation -- and in doing so, to identify men who are at high risk for developing the disease," so prostate cancer can be detected in time to cure it. Men with HPC tend to develop the disease far sooner -- even as young as their late thirties or early forties -- than other men.
Unfortunately, by the time these men even start routine screening for prostate cancer, it may already be too late to cure it.
"Next, finding out the function of this gene should enable us to understand what causes prostate cancer in general," Walsh continues. "Once we know what the gene does, this could lead to new strategies of preventing the disease, or treating advanced cancer."
An estimated 250,000 American men may carry the defective gene, named HPC-1, says William B. Isaacs, Ph.D., associate professor of urology and oncology, and the senior author who directed the study, which was published in the journal Science. These men appear to have extremely high odds -- a nearly 90 percent likelihood -- of developing prostate cancer by age 85, he says.
The gene doesn't appear to discriminate: "It may be active over a wide variety of geographic regions and ethnic backgrounds," Isaacs says. In the study, the susceptibility was found in Caucasian and black men scattered throughout the U.S., as well as Caucasians in Canada and Sweden. However, as Walsh points out, this raises still more questions: "We know that prostate cancer is more common in African Americans. Does this increased risk have a genetic basis -- and if so, is this the gene that's involved? We hope to address this and the overall importance of ethnic heritage in the near future. For this reason, we're anxious to find African-American families with strong family histories of prostate cancer." (If your family can help, please enter the study -- see below.)
The difficulty of this task, of looking for a lone defective gene out of the thousands of genes that remain unexplored in the human body, is awesome. Donald Coffey, Ph.D., director of research, likens the quest for HPC-1 to searching for a single misspelled word in 17 sets of the Encyclopedia Britannica -- 323 volumes. Homing in on the gene thus far -- by narrowing it's location down to a small portion of one chromosome -- is the equivalent of reducing the search for the faulty word from 380,490 pages to a mere 400 pages. A monumental step, says Walsh, "but there is still much more to do" -- finding the gene, and looking for other genes that may be involved.
How the Search Began
Prostate cancer is a confoundingly common disease. That's why, for years, scientists downplayed the idea that (just like more conspicuous illnesses such as hemophilia) it could be inherited -- even though it was known to run in families. Thirty years ago, Mormon genealogists in Utah noted that prostate cancer seemed to "cluster" in families -- and that, among familial cancers, this clustering of prostate cancer was actually more common than breast or colon cancer (yet both of these were recognized to have a hereditary predisposition).
But for some reason, prostate cancer got lumped in the category of ailments that simply come with old age, says Walsh. With this perception muddying the water, "these observations went relatively unexplored for a couple of decades -- largely because prostate cancer was so common in older men."
In the 1980s, Walsh began to see increasingly younger men for surgical treatment of prostate cancer, and was struck by how many of them had a family history of the disease. Then, in 1986, he met a 49-year-old patient with a tragic, unforgettable legacy: "He told me that every male member of his family had died of prostate cancer: His father, his father's three brothers, and his grandfather," says Walsh. "At that time, virtually every physician in the United States could tell you that a woman's risk for breast cancer was increased twofold if her mother or sister had it. I wondered why similar information wasn't available about prostate cancer."
So Walsh set out to find some answers, initiating the first of a series of studies, ably led by Bob Carter, an M.D.-Ph.D. student, and Gary Steinberg, a former resident, and aided by pediatric geneticist Barton Childs, M.D., and genetic epidemiologist Terri Beatty. The first question: Would the observations that had been pretty much limited to Utah Mormons hold true with a larger, more diverse group of men? A study of 691 patients, who had come to Hopkins for a radical prostatectomy, confirmed that having a family history of prostate cancer did indeed increase a man's risk of developing the disease. Next, the Hopkins researchers ruled out environmental factors; further, their results strongly suggested that increased susceptibility to prostate cancer could be inherited from either parent. They then went on to define and characterize Hereditary Prostate Cancer, showing the clear link between family history and a man's probability of developing prostate cancer. (Briefly, if your father or brother has prostate cancer, your risk is two times greater than the average American man's which is about 13 percent. It goes up from there: Depending on the number of affected relatives you have and the age at which they develop the disease, your risk could be as high as 50 percent if you are in a family that meets the criteria for HPC -- if you have at least three close relatives, such as father and two brothers affected, or two relatives if both were younger than 55 years old; or if your family has a disease in three generations -- a grandfather, father, or brother.)
Then came this study. Out of a pool of 2,500 families that met the criteria for HPC came an elite group of 91 families -- hand-picked and rigorously screened by Walsh and behavioral scientist Sally Isaacs. Sadly, the families selected for the study were those hardest-hit be prostate cancer -- so there could be no mistaking hereditary cancer for, as Walsh puts it, "simply bad luck," in which several men in the same family happened to develop the disease. The families filled out detailed questionnaires about their health, occupations and family history, and sent blood samples to Hopkins.
"We had what no one else had," says William Isaacs, "the families. They were our gold mine." It was there DNA that pointed to the marker, or signpost for the gene. It will be their DNA that -- "with a lot of hard work and a little luck," as Isaacs says -- will lead to the gene itself.
Note: In HPC families, men should have a digital rectal examination and PSA test every year, beginning at age 40. If three or more members of you family have had prostate cancer, you may want to register your name with the Johns Hopkins Hereditary Prostate Cancer Study. We will provide you with regular updates about our research progress. To receive this free information, or to find out more about this work, write to the Johns Hopkins Hereditary Prostate Cancer Study at the Brady Urological Institute, The Johns Hopkins Hospital, Baltimore, Md., 21287-2101.
"Major Susceptibility Locus for Prostate Cancer on Chromosome 1 Suggested by a Genome-Wide Search," in Science, Vol. 274, pp. 1371-1373, Nov. 22, 1996. Jeffery R. Smith, Diha Freije, John D. Carpten, Henrik Gronberg, Jianfeng Xu, Sarah D. Isaacs, Michael J. Brownstein, G. Steven Bova, Hong Guo, Prioska Bujnovszky, Deborah R. Nusskern, Jan-Erik Damber, Anders Bergh, Monika Emanuelsson, Olli P. Kallioniemi, Jennifer Walker-Daniels, Joan E. Bailey-Wilson, Terri H. Beaty, Deborah A. Meyers, Patrick C. Walsh, Francis S. Collins, Jeffery M. Trent, William B. Isaacs.