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.
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.
for decades that melanoma is less aggressive in some patients and more
aggressive in others, but we haven't known why," said NHGRI Senior
who led the research team. "Our study provides clues to the biology
of melanoma which open a new window on this terrible disease."
is a highly varied disease, people have looked at it as a continuous spectrum,"
added NHGRI scientist Dr.
one of the lead authors of the Nature paper. "Until now, there were
no discrete subgroups that could be identified in populations of people
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.
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.
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
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
"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
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
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."
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