Milan Radovich1, Curtis Pickering2, Ina Felau3, Gavin Ha4, Hailei Zhang4, Heejoon Jo5, Katherine A. Hoadley5, Pavana Anur6, Jiexin Zhang2, Mike Mclellan7, Reanne Bowlby8, Thomas Matthew9, Ludmila Danilova10, Apurva M. Hedge2, Jaegil Kim4, Max Leiserson11, Geetika Sethi12, Charles Lu7, Michael Ryan2, Xiaoping Su2, Andrew D. Cherniack4, Gordon Robertson8, Rehan Akbani2, Paul Spellman6, John N. Weinstein2, David Neil Hayes5, Ben Raphael11, Tara Lichtenberg13, Kristen Leraas13, Jean Claude Zenklusen3, Junya Fujimoto2, Cristovam Scapulatempo-Neto14, Andre L. Moreira15, David Hwang16, James Huang17, Mirella Marino18, Robert Korst19, Giuseppe Giaccone20, Yesim Gokmen-Polar1, Sunil Badve1, Arun Rajan21, Philipp Ströbel22, Nicolas Girard23, Ming S. Tsao24, Alexander Marx25, Anne S. Tsao2, Patrick J. Loehrer1
1Indiana University Simon Cancer Center, Indianapolis, IN, USA;2MD Anderson Cancer Center, Houston, TX, USA;3National Cancer Institute, Bethesda, MD, USA;4Broad Institute, Cambridge, MA, USA;5University of North Carolina at Chapel Hill, Chapel Hill, NC, USA;6Oregon Health & Science University, Portland, OR, USA;7McDonnell Genome Institute at Washington University, St. Louis, MO, USA;8Canada’s Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver, BC, Canada;9University of California, Santa Cruz, CA, USA;10John Hopkins University, Baltimore, MD, USA;11Brown University, Providence, RI, USA;12Institute for Systems Biology, Seattle, WA, USA;13Nationwide Children’s Hospital, Columbus, OH, USA;14Barretos Cancer Hospital, Barretos, Brazil;15New York University, New York, NY, USA;16University Health Network, Toronto, ON, Canada;17Memorial Sloan Kettering Cancer Center, Manhattan, NY, USA;18Regina Elena National Cancer Institute, Rome, Italy;19Valley Health System, Ridgewood, NJ, USA;20Georgetown University, Washington, DC, USA;21National Cancer Institute, Bethesda, MD, USA; 22University Medical Center, Gottingen, Germany;23Hospices Civils De Lyon, Institute of Oncology, Lyon, France;24Princess Margaret Cancer Centre, Toronto, ON, Canada;25Institut De Pathologie, Universitaets Medizin Mannheim, Mannheim, Germany
Background: Thymoma and thymic carcinoma are the most common malignancies of the anterior mediastinum. Additionally, thymoma has a unique association with autoimmune disorders, notably myasthenia gravis (MG). Histologic classification of thymic epithelial tumors (TETs) has been largely based on the gross description of the epithelial cell appearance and the relative abundance of associated lymphocytes. A comprehensive molecular analysis of TETs has not heretofore been conducted.
Methods: The TCGA Research Network conducted multi-platform analyses of 117 TETs (thymoma =105; thymic carcinoma =10 and micronodular thymoma =2), which included whole-exome, transcriptome, methylome and targeted proteome analysis. Patient characteristics: median age =60 years (range, 17–84 years); M:F (%) =52:48; Masaoka stage {I [36], IIA [39], IIB [19]; III [15]; IVA [1]; IVB [5]}; MG was present in 32 patients. No patient had prior therapy for metastatic disease, but 14 had prior chemotherapy and 39 had prior radiation therapy in the adjuvant setting. WHO histologic classification (blinded review) revealed A =10; AB =48, B1 =12, B2 =25, B3 =10, micronodular thymoma =2 and TC =10.
Results: Thymoma has the lowest tumor mutation burden among adult malignancies in the TCGA. A unique transcription factor, GTF2I, was the most commonly observed mutation in WHO Types A and A/B. All GTF2I mutations were exclusively at the amino acid 424 locus. This is the only tumor with this specific mutation within the entire TCGA database. Differential expression of the RNA and protein data revealed dysregulation of several oncogenic pathways in GTF2I mutants vs. wild-type. Oncogenic HRAS, NRAS and TP53 mutations were also observed, but at a lower frequency among all TETs. We further describe an MSI-unstable thymic carcinoma that was hyper-mutated. Using multi-platform analyses, four distinct molecular-driven subtypes of TETs were identified that strongly correlated with the current WHO histologic classification and were associated with survival. Genomic hallmarks of these subtypes were identified to aid pathologic diagnosis. Lastly, when comparing MG-positive vs. -negative thymomas, we observed increased aneuploidy and overexpression of muscle auto-antigens in MG-positive tumors, providing a pathophysiologic link between thymoma and MG.
Conclusions: Based on molecular analysis, four clusters were identified that correlated strongly with the current WHO Histologic Classification. Also identified was a unique mutation in GTF2I, which was associated with WHO Type A and A/B thymoma. Lastly, a molecular link between MG and thymoma characterized by increased aneuploidy and tumoral over-expression of muscle auto-antigens was observed. This international effort represents the largest and most comprehensive molecular analysis of TETs conducted to date is expected to have important clinical and translational implications for this rare disease.
Keywords: TCGA, genomics; myasthenia gravis (MG)
doi: 10.21037/med.2017.AB007
