Tuesday, September 1, 2009
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 cancer.
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.
Crystal structure of the ERBB4 kinase, the product of a gene that is frequently mutated in melanoma. Credit: NCBI
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 Dr. Rosenberg.
"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 ERBB4 mutations."
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 MMP genes.
Study abstract
Original article
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SOURCE: National Institutes of Health