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NIH-Led Team IDs Mutations That May Improve Skin Cancer Treatment

NEW YORK (GenomeWeb News) – Mutations in the protein tyrosine kinase gene ERBB4 contribute to — and may provide hints about treating — a subset of melanoma, according to a paper by researchers from the National Institutes of Health and Johns Hopkins University that appeared in the advanced, online edition of Nature Genetics this week.

The team sequenced protein tyrosine kinase or PTK genes in 29 individuals with melanoma. Their search uncovered dozens of somatic mutations affecting the kinase domain of 19 different PTK genes. When they looked at the same 19 genes in another 79 melanoma patients, the researchers found that almost a fifth of those tested harbored mutations in ERBB4.

And, they reported, knocking down the mutated form of ERBB4 or using a drug that targeted the gene slowed the growth of melanoma cell lines, suggesting it might be useful to evaluate ERBB4 status in melanoma patients.

Researchers at the NIH Intramural Sequencing Center sequenced all 86 PTK family genes in tumor samples from 29 individuals with melanoma, picking out somatic mutations by comparing the tumor with matched normal tissue.

Overall, the team detected 30 somatic mutations affecting 19 different PTK genes. When the team sequenced the coding regions of these 19 genes in another 79 melanoma patients, they found 99 non-synonymous mutations.

In particular, 19 percent of the individuals had mutations affecting ERBB4 (also known as HER4), while ten percent carried PTK2B or FLT3 mutations.

Of these, the ERBB4 appeared to be the most severely mutated. As such, the team decided to investigate whether mutations in that gene influenced melanoma growth and/or treatment response, focusing on seven different missense mutations in ERBB4.

The researchers found that the growth of melanoma cell lines containing ERBB4 mutations was curbed when they knocked down the mutated form of the gene using small interfering RNA.

The team was also able to slow the growth of the melanoma cell lines by treating them with the ERBB4-inhibiting drug lapatinib, sold as Tykerb by GlaxoSmithKline.

"We have found what appears to be an Achilles' heel of a sizable share of melanomas," senior author Yardena Samuels, a researcher with the National Human Genome Research Institute's Cancer Genetics Branch, said in a statement.

The team plans to do a clinical trial looking at whether lapatinib is effective for treating melanoma in patients who carry ERBB4 mutations. Steven Rosenberg, chief of surgery at the National Cancer Institute and a researcher with the NIH's clinical center will reportedly head the trial.

"We envision a day when each cancer patient will have therapies tailored to the specific genetic profile of his or her tumor," NHGRI Director Eric Green, said in a statement. "Ultimately, this should lead to more effective and less toxic approaches to cancer care." Green was not directly involved in the current study, but heads the NIH sequencing center that generated the sequence data.

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