Transcriptional Profiling of Malignant Melanoma Reveals Novel and Potentially Targetable Gene Fusions

SIMPLE SUMMARY: Malignant melanoma is a complex disease that is estimated to claim over 7000 lives in the United States in 2021. Although recent advances in genomic technology have helped with the identification of driver variants, molecular studies and clinical trials have often focused on prevalent alterations, such as the BRAF-V600E mutation. With the inclusion of whole transcriptome sequencing, molecular profiling of melanomas has identified gene fusions and revealed gene expression profiles that are consistent with the activation of signaling pathways by common driver mutations. Patients harboring such fusions may benefit from currently approved targeted therapies and should be considered in the design of future clinical trials to further personalize treatments for patients with malignant melanoma. ABSTRACT: Invasive melanoma is the deadliest type of skin cancer, with 101,110 expected cases to be diagnosed in 2021. Recurrent BRAF and NRAS mutations are well documented in melanoma. Biologic implications of gene fusions and the efficacy of therapeutically targeting them remains unknown. Retrospective review of patient samples that underwent next-generation sequencing of the exons of 592 cancer-relevant genes and whole transcriptome sequencing for the detection of gene fusion events and gene expression profiling. Expression of PDL1 and ERK1/2 was assessed by immunohistochemistry (IHC). There were 33 (2.6%) cases with oncogenic fusions (14 novel), involving BRAF, RAF1, PRKCA, TERT, AXL, and FGFR3. MAPK pathway-associated genes were over-expressed in BRAF and RAF1 fusion-positive tumors in absence of other driver alterations. Increased expression in tumors with PRKCA and TERT fusions was concurrent with MAPK pathway alterations. For a subset of samples with available tissue, increased phosphorylation of ERK1/2 was observed in BRAF, RAF1, and PRKCA fusion-positive tumors. Oncogenic gene fusions are associated with transcriptional activation of the MAPK pathway, suggesting they could be therapeutic targets with available inhibitors. Additional analyses to fully characterize the oncogenic effects of these fusions may support biomarker driven clinical trials.