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

  • Nat Commun. 2017 Oct 30;8(1):1197. doi: 10.1038/s41467-017-01178-z.
Martin G Dalin  1  2  3 ,  Nora Katabi  4 ,  Marta Persson  5 ,  Ken-Wing Lee  1 ,  Vladimir Makarov  1  6 ,  Alexis Desrichard  1  6 ,  Logan A Walsh  1 ,  Lyndsay West  7 ,  Zaineb Nadeem  1  7 ,  Deepa Ramaswami  1  7 ,  Jonathan J Havel  1  6 ,  Fengshen Kuo  1  6 ,  Kalyani Chadalavada  8 ,  Gouri J Nanjangud  8 ,  Ian Ganly  7 ,  Nadeem Riaz  6  9 ,  Alan L Ho  10 ,  Cristina R Antonescu  4 ,  Ronald Ghossein  4 ,  Göran Stenman  5 ,  Timothy A Chan  11  12  13 ,  Luc G T Morris  14  15  16
Affiliations
  • 1. Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA.
  • 2. Department of Pediatrics, Institute of Clinical Sciences, University of Gothenburg, 41685, Gothenburg, Sweden.
  • 3. Queen Silvia Children's Hospital, Sahlgrenska University Hospital, 41685, Gothenburg, Sweden.
  • 4. Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA.
  • 5. Sahlgrenska Cancer Center, Department of Pathology and Genetics, University of Gothenburg, 40530, Gothenburg, Sweden.
  • 6. Immunogenomics and Precision Oncology Platform, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA.
  • 7. Head and Neck Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA.
  • 8. Molecular Cytogenetics Core Facility, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA.
  • 9. Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA.
  • 10. Head and Neck Medical Oncology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA.
  • 11. Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA. [email protected].
  • 12. Immunogenomics and Precision Oncology Platform, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA. [email protected].
  • 13. Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA. [email protected].
  • 14. Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA. [email protected].
  • 15. Immunogenomics and Precision Oncology Platform, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA. [email protected].
  • 16. Head and Neck Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA. [email protected].
PMID: 29084941 DOI: 10.1038/s41467-017-01178-z
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.

Products