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Spitzoid Melanoma Sequencing Reveals MEK Inhibitor Target

NEW YORK (GenomeWeb) – A team from the US and France has demonstrated the potential of using clinical sequencing to inform treatment for spitzoid melanoma, a form of melanoma that typically turns up in children and adolescents.

"Our analysis of a single index case highlights the value of comprehensive sequencing in identifying previously undescribed somatic alterations that can impact treatment," first and co-corresponding author Scott Newman, a computational biology researcher at St. Jude Children's Research Hospital, and his colleagues wrote in a study published online today in Nature Medicine.

Past studies of spitzoid melanoma have identified driver gene fusions involving genes such as BRAF, ROS1, and ALK, the team noted, though it is typically not possible to pick up driver alterations in roughly half of cases.

For their analysis, the researchers used clinical whole-genome, exome, and/or RNA sequence data on samples from an 11-year-old boy with locally recurrent spitzoid melanoma who had gone through prior treatment with conventional therapeutic approaches, uncovering an in-frame MAP3K8 gene fusion.

Because MAP3K8 codes for a serine-threonine kinase enzyme involved in MEK activation, the team speculated that the initial patient profiled may respond to the small molecule MEK 1/2 inhibitor trametinib. Following oral treatment with trametinib, the boy did show a decrease in the size and number of spitzoid melanoma lesions, though he ultimately discontinued treatment due to cardiotoxicity and diminished efficacy.

"Therapeutic targeting of the MAPK signaling cascade is of great relevance to melanoma, and the presence of a MAP3K8 abnormality may predict a response to trametinib," the authors wrote. "The in vivo response in our patient, although transient, provided preliminary support for the efficacy of MEK inhibition in patients that harbor this lesion; however, future clinical studies are necessary to explore this further."

When the researchers went on to assess 51 samples from another 49 spitzoid melanoma patients with RNA sequencing, meanwhile, they identified in-frame fusions involving MAP3K8 in almost one-third of cases. They noted that each of those fusions involved transcript fusions that replaced or truncated an autoinhibitory exon of MAP3K8.

"MAP3K8 disruption leading to loss or replacement of the final exon was the most prevalent alteration in the 49 cases analyzed," the authors wrote. "Rearrangements were found in both atypical Spitz tumor and spitzoid melanoma cases; they may also be found in benign nevi, as are other driving mutations or fusions, but suitable benign Spitz samples were not available for assessment."

To search for other cancer-related alterations in MAP3K8, the team sifted through data from the COSMIC and CBioPortal databases, as well as RNA-seq data for 472 melanoma patients from the Cancer Genome Atlas project. In seven of the 472 melanoma cases from TCGA, for example, the expression profiles pointed to MAP3K8 fusions or truncations.

From these and other findings, the authors noted the that "MAP3K8 rearrangements — uncovered by comprehensive clinical sequencing of a single case — are the most common genetic event in spitzoid melanoma, are present in adult melanomas, and could be amenable to MEK inhibition."