RT Journal Article
SR Electronic
T1 Multi-dimensional genomic analysis of myoepithelial carcinoma identifies prevalent oncogenic gene fusions
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 148072
DO 10.1101/148072
A1 Martin G. Dalin
A1 Nora Katabi
A1 Marta Persson
A1 Ken-Wing Lee
A1 Vladimir Makarov
A1 Alexis Desrichard
A1 Logan A. Walsh
A1 Lyndsay West
A1 Zaineb Nadeem
A1 Deepa Ramaswami
A1 Jonathan J. Havel
A1 Fengshen Kuo
A1 Kalyani Chadalavada
A1 Gouri J. Nanjangud
A1 Nadeem Riaz
A1 Alan L Ho
A1 Cristina R. Antonescu
A1 Ronald Ghossein
A1 Göran Stenman
A1 Timothy A. Chan
A1 Luc G.T. Morris
YR 2017
UL http://biorxiv.org/content/early/2017/06/09/148072.abstract
AB 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.