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

Myoepithelial carcinoma (MECA) is an aggressive type of salivary gland cancer with largely unknown molecular features. There are no active systemic therapies currently available, and recurrent or metastatic disease is generally incurable. MECA may arise de novo or result from oncogenic transformation of a pre-existing pleomorphic adenoma (MECA ex-PA). In this study, we comprehensively analyzed the spectrum of molecular alterations in MECA using whole exome sequencing, RNA sequencing and array comparative genomic hybridization. Our analyses revealed a low mutational load (0.5/MB), but a high prevalence of fusion genes (28/40 tumors; 70%). Many tumors (21/40; 53%) harbored translocations involving the PLAG1 oncogene, which were associated with PLAG1 overexpression. The novel TGFBR3-PLAG1 fusion was found in 6 (15%) cases, and was specific for MECA de novo tumors or the malignant component of MECA ex-PA. This fusion was associated with overexpression of both TGFBR3 and PLAG1, was not found in 723 other salivary gland tumors, and exhibited a tumorigenic phenotype in vitro. The FGFR1-PLAG1 fusion was enriched 15-fold in MECA ex-PA compared to PA. We discovered other novel PLAG1 translocations, including ND4-PLAG1, which is to our knowledge the first reported oncogenic fusion between mitochondrial and nuclear DNA. One tumor harbored a novel MSN-ALK fusion, which was tumorigenic in vitro, and targetable with ALK inhibitors. Furthermore, we found that copy number alterations (CNAs) were more common in MECA ex-PAs than in MECA de novo tumors, and a high number of CNAs was associated with poor survival. We found that several fusion genes were associated with potentially immunogenic neoepitopes, suggesting that neoantigen-based therapies may have value in MECA despite low mutational load. Together, our findings nominate PLAG1 and ALK-targeted therapies for further investigation in MECA, and provide a framework for the next steps of diagnostic and therapeutic research in this lethal cancer.