Do the Math: Genetic Risks Add Up
New Findings May Lead to First-Ever Genetic Test for Prostate Cancer
Each genetic "trouble spot" makes cancer more likely.
From left: Kathleen Wiley, William Isaacs, Sarah Isaacs.
Family History and Prostate Cancer
Hopkins scientists have discovered that having a family history of prostate cancer does indeed increase a man’s risk of developing the disease, and that increased susceptibility to it can 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 getting the disease.
Although the percentage of “purely inherited” cases of prostate cancer is low, what happens to the genes in these men is very important, because it may also happen, over time and aided by countless lifestyle and dietary choices, to the vast majority of men who develop prostate cancer.
Until about 40 years ago, when genealogists in Utah noticed that prostate cancer seemed to cluster in families, nobody thought that prostate cancer might be hereditary. Unfortunately, the disease is so common — more than 200,000 American men are diagnosed with it each year — that for many years, scientists couldn’t see past the numbers. In 1986, Patrick C. Walsh, M.D., University Distinguished Service Professor of Urology, began to see increasingly younger men with this “old man’s disease.” Many of them had a family history of prostate cancer; one of them had a particularly hard legacy: “Every male in his family had died of prostate cancer — his father, his father’s three brothers, and his grandfather,” says Walsh. “It seemed odd to me that we knew nothing about the role of family history on a man’s risk of getting prostate cancer.”
So began a series of studies at Hopkins, and the dawn of a genetics powerhouse, built around the work of William B. Isaacs, Ph.D., Don Coffey, Ph.D., and others who set out to answer Walsh’s questions, using data gathered at first from his radical prostatectomy patients, and then from men around the world.
In numerous studies over the last two decades, Isaacs and colleagues kept learning more about prostate cancer genetics — finding genes that seemed to be “prostate cancer genes,” for example — but the idea of a genetic test for prostate cancer seemed like an idea that would never happen. Now, for the first time, it doesn’t seem so far away.
Risk Factor, Plus Risk Factor, Plus…
Figuring out the genetic risk factors for prostate cancer is like making a highly detailed model of a house. First, you go room by room. In this case, the rooms are chromosomes, and over many years of analyzing volumes of computerized data, certain areas have emerged as trouble spots. Then, you go foot by foot, and then inch by inch. On a much tinier and more precise scale, it’s akin to reporting that the second floorboard from the left in the dining room squeaks, and then, using a magnifying glass, finding out that two nails are missing.
This is what Isaacs, the William Thomas Gerrard, Mario Anthony Duhon and Jennifer and John Chasty Professor of Urology, has done, except his hard work and achievement are much more difficult to describe adequately. First, looking at blood and tissue samples taken from men and families with a history of prostate cancer, he and colleagues found some chromosomes that appeared to be suspicious. Then they found more specific areas that seemed to be implicated — three of them on the long arm of chromosome 8, and two on the long arm of chromosome 17. Then, in a study recently published in the New England Journal of Medicine, Isaacs and colleagues “did the math.” They discovered that while having one of these trouble spots — called single-nucleotide polymorphisms (SNPs, pronounced “snips”) might add just a little to a man’s risk of getting prostate cancer, the risk is cumulative: It goes up, bit by bit, the more risk factors he has.
It’s like reporting that the second floorboard from the left in the dining room squeaks, and then, using a magnifying glass, finding out that two nails are missing.
Having just one of these genetic trouble spots adds just a little to a man’s risk of getting prostate cancer, but the risk is cumulative. It goes up, bit by bit, the more risk factors he has.
“When the SNPs are combined, the association is stronger,” says Isaacs. In this international genetic study, scientists from the U.S. and Sweden studied 2,893 men with prostate cancer, and 1,781 randomly selected men who did not have prostate cancer. They looked at 16 SNPs from five chromosomal regions in these men.
“It turns out that each SNP independently increases a man’s risk of developing prostate cancer slightly,” says Isaacs. “But men who inherit four or five of these have a risk of developing prostate cancer that is 4.5 times higher than men who don’t have these SNPs.”
When a sixth variable — a positive family
history of prostate cancer — was added to the mix, a man’s risk of getting prostate cancer was almost ten times higher. “Even though this highest risk group was very small, representing only 1.4 percent of our study population, these results are highly significant,” says Isaacs. “Until now, there has been no genetic test that could be used to guide an individual patient.” Isaacs and colleagues believe that still more individual risk factors will be found in the future — and that one day, based on their findings, they will be able to test for these factors, too, in men at risk of developing prostate cancer.