Multi-dimensional genomic analysis of myoepithelial carcinoma identifies prevalent oncogenic gene fusions

Abstract

Abstract Myoepithelial carcinoma (MECA) is an aggressive type of salivary gland cancer with largely unknown molecular features. MECA may arise de novo or result from oncogenic transformation of a pre-existing pleomorphic adenoma (MECA ex-PA). We comprehensively analyzed the molecular alterations in MECA with integrated genomic analyses. We identified a low mutational load (0.5/MB), but a high prevalence of fusion oncogenes (28/40 tumors; 70%). We found FGFR1-PLAG1 in 7 (18%) cases, and the novel TGFBR3-PLAG1 fusion in 6 (15%) cases. TGFBR3-PLAG1 was specific for MECA de novo tumors or the malignant component of MECA ex-PA, was absent in 723 other salivary gland tumors, and promoted a tumorigenic phenotype in vitro. We discovered other novel PLAG1 fusions, including ND4-PLAG1, which is an oncogenic fusion between mitochondrial and nuclear DNA. One tumor harbored an MSN-ALK fusion, which was tumorigenic in vitro, and targetable with ALK inhibitors. Certain gene fusions were predicted to result in neoantigens with high MHC binding affinity. A high number of copy number alterations was associated with poorer prognosis. Our findings indicate that MECA is a fusion-driven disease, nominate TGFBR3-PLAG1 as a hallmark of MECA, and provide a framework for future steps of diagnostic and therapeutic research in this lethal cancer.