Scientists Discover Gene Linked to Higher Rates of ...



Scientists Discover Gene Linked to Higher Rates of Prostate Cancer

By NICHOLAS WADE

Published: May 8, 2006

A team of scientists says it has detected a variant gene associated with prostate cancer, a finding that may make possible a diagnostic test to help decide which patients are the best candidates for aggressive treatment.

The discovery, by DeCode Genetics, a gene-finding company in Iceland, may also help explain why African-Americans, in whom the variant is more common, have a greater incidence of the disease.

Prostate cancer is a common disease with many causes, both genetic and environmental. Detection of the underlying genes is difficult because each seems to have only a small effect on the risk of getting the disease. Several candidate genes have been identified in one family or population but have generally not been confirmed by researchers trying to replicate the finding in other populations.

The new variant, described online yesterday in the journal Nature Genetics, was first found in Icelandic men and then detected in Sweden and in two populations in the United States. David Altshuler, a medical geneticist at the Broad Institute in Cambridge, Mass., said the result was statistically convincing and, because it was tested in four populations, "a model for how these things should be done."

The variant is carried by about 13 percent of men of European ancestry. It raises the risk of getting prostate cancer by 60 percent, compared with men who are not carriers, and accounts for about 8 percent of all cases, according to the scientists, led by Laufey T. Amundadottir of DeCode.

Among African-Americans, the variant carries the same risk but is twice as common. This could explain "a significant part" of the reason that prostate cancer is more common in this population, said Dr. Kari Stefansson, DeCode's chief executive. Dr. Stefansson said the variant was "the first major gene in prostate cancer and the first to be replicated in many populations."

William B. Isaacs, a prostate cancer expert at Johns Hopkins University, called the new finding "very exciting" and added that until now "there haven't really been any clear-cut examples of genes identified by one group and reproduced across multiple study populations."

The new variant was not especially common in Icelandic men with a harmless enlargement of the prostate gland, called benign prostatic hyperplasia, indicating that its association was only with malignant forms of the disease. Dr. Stefansson said this might explain why African-Americans more often died from the disease, in addition to having a higher incidence than white Americans.

The company plans to develop a diagnostic test, based on the new variant, to help physicians decide how aggressively to treat the disease, especially in men over 70, on the assumption that men who carry the variant are more likely to develop serious cancer.

Many men in this age group "have competing morbidities," Dr. Isaacs said, and go on to die of other causes, in which case it would be best to leave the prostate cancer untreated. But in some, the cancer is malignant, and if such an outcome could be predicted, aggressive treatment like radiation or removal of the prostate gland would be more worthwhile.

Dr. Isaacs and Dr. Altshuler said that the idea of a diagnostic test was reasonable but that more studies would be needed to show whether the information would be of practical clinical use.

The new variant lies at a site on the DNA of Chromosome 8. Until now no gene had been recognized at this site, but DeCode researchers have found hints of one active in the prostate gland. It is unlike any other known gene, so it is not yet possible to say what the gene normally does or how the new variant contributes to prostate cancer.

November 18, 2005 (NY Times)

Timid Mice Made Daring by Removing One Gene

By BENEDICT CAREY

Scientists working with mice have found that by removing a single gene they can turn normally cautious animals into daring ones, mice that are more willing to explore unknown territory and less intimidated by sights and sounds that they have learned can be dangerous.

The surprising discovery, being reported today in the journal Cell, opens a new window on how fear works in the brain, experts said. Gene therapy to create daredevil warriors is likely to remain the province of screenwriters, but the new findings may help researchers design novel drugs to treat a wide array of conditions, from disabling anxiety in social settings to the sudden flights of poisoned memory that can persist in the wake of a disaster, an attack or the horror of combat.

The discovery may well prove applicable to humans, the experts said, because the brain system that registers fear is similar in all mammals. Moreover, the genetic change did not appear to affect the animals' development in other ways.

"Potential clinical applications could be quite important" for people with "fear-related mental disorders," said Dr. Gleb Shumyatsky, an assistant professor of genetics at Rutgers, who led a team that included investigators from Columbia, Harvard, the Howard Hughes Medical Institute and the Albert Einstein College of Medicine. Brain scientists who were not involved in the study said the study's finding was unexpected.

"The way I see it, there are three types of studies in science: one that moves a theory along, one that closes it and another that opens a new door altogether," said Dr. Thomas Insel, director of the National Institute of Mental Health, which helped finance the research. "This one opens a new chapter, introducing an entirely new molecular candidate for the study of anxiety, and we're going to be hearing a lot about it in the next 10 years."

The researchers found the fear-related gene by analyzing brain tissue, in particular the tiny prune-shaped region called the amygdala, which previous studies had shown to be especially active when animals and humans were afraid or anxious. They found that a protein called stathmin, produced by the stathmin gene, was highly concentrated in the amygdala but hard to detect elsewhere in the brain.

Using genetic engineering, the scientists removed the gene from mice and bred a line of the animals, all missing the same gene. Those animals developed into normal adults, as far as the researchers could tell, and learned as ably on standard tests as a group of normal mice. In one test, they learned to expect a small shock to their feet after hearing a loud tone. "They looked normal," Dr. Shumyatsky said. "They weren't stupid. They would run away if you tried to pick them up." But when presented with the same loud tone 24 hours later, the genetically engineered mice froze in place - a standard measure of learned fear - only about 60 percent as long as the control group. When left alone on an unfamiliar white surface, the engineered mice also spent about twice as long exploring as did the normal mice. This "open field" test is standard measure of innate caution.

To be sure that it was the gene change and not some other quality that explained the differences, the researchers tested hearing and pain sensitivity in the altered mice. Both were normal.

In the paper, the authors suggest that stathmin, the protein that the engineered mice were missing, may help brain cells form new memories in the amygdala, where unconscious fears appear to be stored. (Conscious memories are filed elsewhere.)

In theory, a drug that inhibits the activity of stathmin could prevent or slow that process. That, in turn, might blunt the impact of traumatic experiences in people who are vulnerable to disabling memories of those experiences.

Reducing stathmin activity in the amygdala might also allow people to overcome innate or learned anxieties. Dr. Shumyatsky said doctors already had a drug that acts on the same brain molecules as stathmin does; it is Taxol, a cancer drug. Taxol works throughout the brain, however, and not exclusively in the amygdala, which the new study suggests is the best target.

"It would be very interesting to study things like this, but it is still very early," Dr. Shumyatsky said. "This study is only a first step." Still, it is a step that could take the study of fear in a new direction. In an e-mail message, Dr. Joseph LeDoux, a neuroscientist at New York University wrote: "While we are a long ways away, it is possible in the future that we will be able to identify amygdala-specific genes that can be used to play a role in amygdala-specific drug therapy. Studies like this are the kind we need in order to get to this point."

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