|NIH Study Reveals New Genetic Culprit in
Deadly Skin Cancer
Sequencing Work Points to New Target for Melanoma Treatment
Drawing on the power of DNA sequencing, National Institutes of
Health researchers have identified a new group of genetic mutations
involved in the deadliest form of skin cancer, melanoma. This discovery
is particularly encouraging because some of the mutations, which
were found in nearly one-fifth of melanoma cases, reside in a gene
already targeted by a drug approved for certain types of breast
In the United States and many other nations, melanoma is becoming
increasingly more common. A major cause of melanoma is thought
to be sun exposure; the ultraviolet radiation in sunlight can damage
DNA and lead to cancer-causing genetic changes within skin cells.
In work published in the September issue of Nature Genetics, a
team led by Yardena Samuels, Ph.D., of the National Human Genome
Research Institute (NHGRI) sequenced the protein tyrosine kinase
(PTK) gene family in tumor and blood samples from people with metastatic
melanoma. The samples were collected by the study's coauthor Steven
Rosenberg, M.D., Ph.D., a leading expert on melanoma and chief
of surgery at the National Cancer Institute (NCI).
The PTK family includes many genes that, when mutated, promote
various types of cancer. However, relatively little had been known
about roles played by PTK genes in human melanoma. The NIH study
was among the first to use large-scale DNA sequencing to systematically
analyze all 86 members of the PTK gene family in melanoma samples.
The team's initial survey, which involved samples from 29 melanoma
patients, identified mutations in functionally important regions
of 19 PTK genes, only three of which had been previously implicated
in melanoma. The researchers then conducted more detailed analyses
of those 19 genes in samples from a total of 79 melanoma patients.
One of the newly implicated genes stood out from the rest. Researchers
detected mutations in the ERBB4 gene (also known as HER4) in 19
percent of patients' tumors, making it by far the most frequently
mutated PTK gene in melanoma. In addition, researchers found that
many ERBB4 mutations were located in functionally important areas
similar to those seen in other PTK oncogenes involved in lung cancer,
brain cancer and gastric cancer.
Next, the researchers moved on to laboratory studies of melanoma
cells with ERBB4 mutations. They found that these melanoma cells
were dependent on the presence of mutant ERBB4 for their growth.
What's more, the melanoma cells grew much more slowly when they
were exposed to a chemotherapeutic drug known to inhibit ERBB4.
The drug, called lapatinib (Tykerb), was approved by the Food and
Drug Administration in 2007 for combination use in breast cancer
patients already taking the drug capecitabine (Xeloda).
Encouraged by their study results, the researchers are planning
a clinical trial using lapatinib in patients with metastatic melanoma
harboring ERBB4 mutations. The clinical trial will be conducted
under the direction of Dr. Rosenberg at the NIH Clinical Center. "This
collaborative study represents an ideal example of how sophisticated
genetic analyses can be translated to the benefit of cancer patients," said
"We have found what appears to be an Achilles' heel of a
sizable share of melanomas," said Dr. Samuels, who is an investigator
in the Cancer Genetics Branch of the NHGRI's Division of Intramural
Research. "Though additional work is needed to gain a more
complete understanding of these genetic mutations and their roles
in cancer biology, our findings open the door to pursuing specific
therapies that may prove useful for the treatment of melanoma with
In addition to ERBB4, the researchers identified two additional
PTK genes, FLT1 and PTK2B, with a relatively high rate of mutations
in melanoma. Each of these genes was mutated in about 10 percent
of the tumor samples studied.
NHGRI Scientific Director Eric D. Green, M.D., Ph.D., pointed
out how such research is helping to lay the groundwork for the
era of personalized medicine. "We envision a day when each
cancer patient will have therapies tailored to the specific genetic
profile of his or her tumor. Ultimately, this should lead to more
effective and less toxic approaches to cancer care," said
Dr. Green, who directs the NIH Intramural Sequencing Center, which
generated the DNA sequence data for the melanoma study.
In addition to NIH scientists, the team included a researcher
from the Johns Hopkins Kimmel Cancer Center in Baltimore.
In May 2009, Dr. Samuel's group reported in Nature Genetics another
large-scale DNA sequencing study of a different group of genes
involved in melanoma, the matrix metalloproteinase (MMP) gene family.
This earlier study found that one gene, MMP-8, thought to spur
cancerous growth actually served to inhibit it. Those findings
are now helping to shape melanoma treatment strategies aimed at
For high resolution micrographs of metastatic melanoma, go to http://www.genome.gov/pressDisplay.cfm?photoID=20152 and http://www.genome.gov/pressDisplay.cfm?photoID=20153.
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NHGRI is one of the 27 institutes and centers at the NIH, an agency
of the Department of Health and Human Services. The NHGRI Division
of Intramural Research develops and implements technology to understand,
diagnose and treat genomic and genetic diseases. Additional information
about NHGRI can be found at its Web site, www.genome.gov.
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Medical Research Agency — includes 27 Institutes and Centers
and is a component of the U.S. Department of Health and Human Services.
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the causes, treatments, and cures for both common and rare diseases.
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