Michael Michal, Faizan Malik, Boulos Mansour, Travis Hattery, Carina Dehner, Petr Martínek, Veronika Hájková, Tomáš Vaněček, John S.A. Chrisinger, Isidro Machado, Natálie Klubíčková, Vaiyapuri P. Sumathi, Tony Ng, Laura M. Warmke, Ming Liang Oon, Fredrik Petersson, Pedram Argani, John Gross, Michal Michal, Cristina R. Antonescu, Josephine K. Dermawan
PURPOSE: Fusion-positive myoepithelial tumors (MET) are clinicopathologically heterogeneous and variably termed mixed tumors and myoepithelial carcinomas. As FET-rearranged METs lack ductal/epithelial differentiation, we test whether FET-rearranged METs are epigenetically distinct from adnexal PLAG1-rearranged METs, which we hypothesize to be analogues of salivary gland METs. EXPERIMENTAL DESIGN: DNA methylation profiling from a multi-institutional cohort of 52 fusion-positive skin, soft-tissue, and bone MET cases was performed and compared with diverse tumor types, including salivary METs. The MET subgroups harbored EWSR1::KLF15, EWSR1/FUS::KLF17, EWSR1::PBX1, EWSR1::PBX3, EWSR1/FUS::POU5F1, SS18::POU5F1, EWSR1::ZNF444, and PLAG1 rearrangements. Pooled clinicopathologic and outcome analysis with new and published cases (total 185) was performed. RESULTS: The MET subgroups showed significant heterogeneity in age, site, and histology. Specifically, EWSR1::KLF15 METs affected predominantly young children (<5 years); EWSR1::PBX1/PBX3 METs were enriched in skin/bone; and EWSR1/FUS::POU5F1, SS18::POU5F1, and EWSR1::KLF15 METs tended to display malignant histology. Conversely, PLAG1-rearranged tumors were predominantly benign, arising in older adults and located in the skin. DNA methylation profiling revealed that FET-rearranged METs were epigenetically related to SS18::POU5F1 METs and FET::NFATC2 sarcomas but entirely distinct from PLAG1-rearranged adnexal and salivary METs. Histologic features were correlated with the degree of genome-wide copy-number variation. The median disease-specific survival was shortest in SS18::POU5F1 (31 months), EWSR1::PBX3 (38 months), and EWSR1::KLF15 (45 months) METs. On multivariate analysis, age <25 years was a significant predictor of worse progression-free survival. CONCLUSIONS: FET-rearranged METs are epigenetically unrelated to cutaneous and salivary gland METs, and their malignant counterparts are best classified as sarcomas rather than carcinomas.