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

Abstract

Myoepithelial carcinoma (MECA) is an aggressive salivary gland cancer with largely unknown genetic features. Here we comprehensively analyze molecular alterations in 40 MECAs using integrated genomic analyses. We identify a low mutational load, and high prevalence (70%) of oncogenic gene fusions. Most fusions involve the PLAG1 oncogene, which is associated with PLAG1 overexpression. We find FGFR1-PLAG1 in seven (18%) cases, and the novel TGFBR3-PLAG1 fusion in six (15%) cases. TGFBR3-PLAG1 promotes a tumorigenic phenotype in vitro, and is absent in 723 other salivary gland tumors. Other novel PLAG1 fusions include ND4-PLAG1; a fusion between mitochondrial and nuclear DNA. We also identify higher number of copy number alterations as a risk factor for recurrence, independent of tumor stage at diagnosis. Our findings indicate that MECA is a fusion-driven disease, nominate TGFBR3-PLAG1 as a hallmark of MECA, and provide a framework for future diagnostic and therapeutic research in this lethal cancer.

• Authors: Martin G Dalin, Nora Katabi, Marta Persson, Ken-Wing Lee, Vladimir Makarov, Alexis Desrichard, Logan A Walsh, Lyndsay West, Zaineb Nadeem, Deepa Ramaswami, Jonathan J Havel, Fengshen Kuo, Kalyani Chadalavada, Gouri J Nanjangud, Ian Ganly, Nadeem Riaz, Alan L Ho, Cristina R Antonescu, Ronald Ghossein, Göran Stenman, Timothy A Chan, Luc G T Morris
• Journal: Nature communications (Nat Commun) Vol. 8 Issue 1 Pg. 1197 (10 30 2017) ISSN: 2041-1723 [Electronic] England
• PMID: 29084941 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• DNA-Binding Proteins
• Oncogene Proteins, Fusion
• PLAG1 protein, human
• FGFR1 protein, human
• Receptor, Fibroblast Growth Factor, Type 1

Topics

• Adolescent
• Adult
• Aged
• Aged, 80 and over
• Cell Line, Tumor
• DNA-Binding Proteins (genetics)
• Female
• Genomics (methods)
• HEK293 Cells
• Humans
• In Situ Hybridization, Fluorescence
• Male
• Middle Aged
• Mutation
• Myoepithelioma (genetics)
• Oncogene Fusion (genetics)
• Oncogene Proteins, Fusion (genetics)
• Receptor, Fibroblast Growth Factor, Type 1 (genetics)
• Salivary Gland Neoplasms (genetics)
• Sequence Analysis, DNA (methods)
• Young Adult