Most melanomas arising in children and adolescents are of the spitzoid subtype. Unlike conventional melanomas in adults, spitzoid tumors are driven by fusions of kinase genes such as ALK, NTRK1/3, MET, RET and ROS1. However, in approximately 50% of cases, no oncogenic driver has been established. This raises the possibility of an, as yet, undescribed oncogene in such tumors.

Clinical whole genome and transcriptome (RNA-Seq) sequencing detected a novel fusion of MAP3K8 in a spitzoid melanoma from an adolescent patient. The fusion preserved the kinase domain of MAP3K8 - a serine threonine kinase that activates MEK/ERK downstream - but replaced the autoinhibitory final exon with an unrelated gene, GNG2. MAP3K8 is a proposed oncogene in breast, ovarian, squamous cell carcinoma and lung cancer and its high expression has been shown to cause resistance to BRAF inhibitors through a MEK-dependent mechanism in melanoma cells (Johannessen et al. 2010 Nature 468:968-72). As the patient had exhausted other therapeutic options, we treated him with the MEK inhibitor, trametinib, and observed a transient response. He later relapsed, and further clinical sequencing showed the MAP3K8-GNG2 fusion had increased in genomic copy number and expression - potentially explaining the acquired resistance to trametinib.

We subsequently screened a cohort of 49 pediatric melanomas with spitzoid features by RNA-Seq, fluorescence in situ hybridization and immunohistochemistry and found that MAP3K8 fusions and truncations were the most common genetic event, supplying the missing kinase driver for 33% of samples. All rearrangements preserved MAP3K8 exons 1-8 but replaced the autoinhibitory final exon with unrelated genetic or intergenic sequence. Strikingly, MAP3K8 rearrangements were mutually exclusive of other known driver mutations such as ALK fusions, further implicating MAP3K8 as a driver oncogene. Transformation assays using NIH 3T3 cells confirmed that the truncated form of MAP3K8 was oncogenic.

Finally, we screened over 11,000 TCGA RNA-Seq samples, and identified seven adult melanomas with analogous MAP3K8 disruptions (1.5% of SKCM samples). Similar to their pediatric counterparts, all seven tumors lacked any other kinase driver mutation. Thus, MAP3K8 rearrangements drive a subset of adult melanomas and these tumors may also be amenable to MEK inhibition. Our experience highlights the need for genome-wide clinical sequencing as MAP3K8 is not covered by popular targeted gene panels.

Citation Format: Scott Newman, Liying Fan, Allison Pribnow, Antonina Silkov, Stephen V. Rice, Seungjae Lee, Ying Shao, Bridget Shaner, Heather Mulder, Joy Nakitandwe, Sheila Shurtleff, Elizabeth Azzato, Gang Wu, Xin Zhou, Raymond Barnhill, John Easton, Kim E. Nichols, David W. Ellison, Downing R. James, Alberto Pappo, Philip M. Potter, Jinghui Zhang, Armita Bahrami. Clinical genome sequencing uncovers potentially targetable truncations and fusions of MAP3K8 in spitzoid and other melanomas [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 731.