An international team led by scientists at the National Human Genome Research Institute (NHGRI) at the National Institutes of Health (NIH) has discovered a genetic "signature" that may help explain how malignant melanoma, a deadly form of skin cancer, can spread to other parts of the body.
Scientists from 11 laboratories in the United States, Australia, and Israel participated in the study, which appears in the August 3 issue of Nature. It is one of the first large-scale studies on cancer genetics to be made possible by the wealth of information generated by the international Human Genome Project.
The research reported in Nature helps explain the mechanisms underlying the metastasis, or spread, of melanoma. And it may ultimately point the way to better diagnosis and treatment of this increasingly common and often fatal disease.
"We've known for decades that melanoma is less aggressive in some patients and more aggressive in others, but we haven't known why," said NHGRI Senior Investigator Dr. Jeffrey Trent, who led the research team. "Our study provides clues to the biology of melanoma which open a new window on this terrible disease."
"Although melanoma is a highly varied disease, people have looked at it as a continuous spectrum," added NHGRI scientist Dr. Michael Bittner, one of the lead authors of the Nature paper. "Until now, there were no discrete subgroups that could be identified in populations of people with melanoma."
Using a novel genetic analysis technology called gene expression profiling, the researchers were able to find a genetic signature, or set of differences in genes, that for the first time divided patients with advanced melanoma into subgroups.
Already, gene expression profiling has been used to identify subsets of lymphoma and leukemia. Such classification of cancer on a molecular level offers the possibility of more accurately determining the prognosis of a particular patient's tumor, based on his or her genetic makeup. It also offers the hope of tailoring therapies to the individual, explained Dr. Trent.
"By learning about what makes each patient's tumor grow, what makes it spread or not spread, hopefully you could tailor therapies to the individual patient rather than use a one-size-fits-all kind of approach," added NHGRI Senior Investigator Dr. Paul Meltzer, the other lead author of the Nature paper.
Gene expression profiling uses devices called DNA microarrays, small glass slides that contain tiny amounts of thousands of known genes. These gene "chips" can then rapidly detect which of those genes are expressed, or turned on, in a single sample of cancer tissue taken from the body or from cancer cells grown in the lab.
In this latest study, almost half a million measurements were taken on nearly 7,000 different genes in melanoma tumors from 40 patients. Computers running sophisticated statistical software were then used to analyze the data from the chips in order to find hidden patterns in gene expression among the tumor samples. Nineteen cancers were found to be very similar in gene expression, differing from the rest of the tumors in the expression of roughly 500 genes. According to the patient histories, tumors in this cluster tended to be less aggressive, suggesting they metastasized less rapidly.
"Using this technology, we could see this discrete subset, which brought into focus the existence of this group that we didn't know about before," said Dr. Meltzer. "We could see the genes that were either turned on or off in that group."
In a related experiment, the researchers then tried to determine the differences in gene expression, which relate to differences in the biological behavior of human melanoma cells cultured in the laboratory. Some of these cancer cells had a much greater invasiveness, or ability to move through layers of other cells -- a process related to the spread of cancer. In addition, some of these same fast-moving cells had a greater ability to form the kind of cord-like structures which resemble the blood vessels necessary to feed tumors as they grow.
"This paper represents a remarkable example of the power of gene expression profiling," commented Dr. Bert Vogelstein, oncology professor at the Johns Hopkins Medical Institutions and a Howard Hughes Medical Institute investigator. "The results not only offer intriguing insights into the biology, but also provide information that should be useful for the management of patients with melanoma."
For NHGRI Director Dr. Francis Collins, the research results provide another example of the value of the Human Genome Project's commitment to providing the deciphered human genetic code to scientists at no cost and without restrictions immediately, as the human genome is sequenced.
"Our goal is to provide high-quality information about the human genetic code so that scientists can use it now to improve diagnosis, prevention and treatment of diseases," he added.
Malignancies of the skin are the most common human cancers, and melanoma is the most serious form of skin cancer. In many parts of the world, melanoma rates are rising faster than those of any other cancer. Experts believe that much of this increase is due to people's greater exposure to the sun's ultraviolet radiation, which can cause misspellings in DNA and, as a result, damage skin cells.
For study co-author Dr. Nicholas Hayward, a cancer geneticist at the Queensland Institute of Medical Research, the trend is particularly troubling. In the northern Australian state of Queensland, an estimated 1 out of 13 males and 1 out of 17 females will develop melanoma during their lifetime.
"The major significance of this work is that there appear to be subgroups of melanoma that behave differently in a biological sense," Hayward said. "These differences may indicate what pathways are involved, which we would need to target for therapeutic intervention."
For Dr. Vernon Sondak, associate professor of surgery at the University of Michigan in Ann Arbor and another author of the Nature paper, the results of this study will change the way scientists think about melanoma and how doctors will treat it in the future.
"This is a glimpse into the secret life of the melanoma cell," Sondak said. "If melanoma is caught in its early stages, it's extremely treatable. But in its later stages, it can be unpredictably aggressive or not aggressive. We now have a new tool for figuring out how the tumor got to be that way."
Institutions participating in the study include NHGRI; National Cancer Institute; University of Iowa Cancer Center; Hewlett-Packard Laboratories in Haifa, Israel; Texas A & M University; Queensland Institute of Medical Research in Queensland, Australia; Barrow Neurological Institute in Phoenix, Arizona; University of Michigan; University of Washington; and University of Arizona Cancer Center.
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