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Study Reveals New Genetic Mutations Involved in Melanoma

BETHESDA, Md -- August 31, 2009 -- Researchers have identified a new group of genetic mutations involved in melanoma. The study is published in the September issue of the journal Nature Genetics.

The 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.

Yardena Samuels, PhD, National Human Genome Research Institute (NHGRI), Bethesda, Maryland, and colleagues sequenced the protein tyrosine kinase (PTK) gene family in tumour and blood samples from people with metastatic melanoma.

The team's initial survey, which involved samples from 29 patients with melanoma, identified mutations in functionally important regions of 19 PTK genes, only 3 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 patients with melanoma.

One of the newly implicated genes stood out from the rest. Researchers detected mutations in the ERBB4 gene (also known as HER4) in 19% of patients' tumours, 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 lapatinib (Tykerb).

"We have found what appears to be an Achilles' heel of a sizable share of melanomas," said Dr. Samuels. "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% of the tumour samples studied.

SOURCE: National Institutes of Health

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