Ollier disease and Maffucci syndrome are non-hereditary skeletal disorders characterized by multiple enchondromas (Ollier disease) combined with spindle cell hemangiomas (Maffucci syndrome). We report somatic heterozygous IDH1 (R132C and R132H) or IDH2 (R172S) mutations in 87% of enchondromas, benign cartilage tumors, and in 70% of spindle cell hemangiomas, benign vascular lesions. In total, 35 of 43 (81%) patients with Ollier disease and 10 of 13 (77%) patients with Maffucci syndrome carried IDH1 (98%) or IDH2 (2%) mutations in their tumors. Fourteen of sixteen patients displayed identical mutations in separate lesions. Immunohistochemistry for mutant R132H IDH1 protein suggested intraneoplastic and somatic mosaicism. IDH1 mutations in cartilage tumors are associated with hypermethylation and downregulation of expression of several genes. Mutations were also found in 40% of solitary central cartilaginous tumors and in four chondrosarcoma cell lines, enabling functional studies to assess the role of IDH1 and IDH2 mutations in tumor formation.

Developmental tumors in children and young adults carry few genetic alterations, yet they have diverse clinical presentation. Focusing on Ewing sarcoma, we sought to establish the prevalence and characteristics of epigenetic heterogeneity in genetically homogeneous cancers. We performed genome-scale DNA methylation sequencing for a large cohort of Ewing sarcoma tumors and analyzed epigenetic heterogeneity on three levels: between cancers, between tumors, and within tumors. We observed consistent DNA hypomethylation at enhancers regulated by the disease-defining EWS-FLI1 fusion protein, thus establishing epigenomic enhancer reprogramming as a ubiquitous and characteristic feature of Ewing sarcoma. DNA methylation differences between tumors identified a continuous disease spectrum underlying Ewing sarcoma, which reflected the strength of an EWS-FLI1 regulatory signature and a continuum between mesenchymal and stem cell signatures. There was substantial epigenetic heterogeneity within tumors, particularly in patients with metastatic disease. In summary, our study provides a comprehensive assessment of epigenetic heterogeneity in Ewing sarcoma and thereby highlights the importance of considering nongenetic aspects of tumor heterogeneity in the context of cancer biology and personalized medicine.

Gastrointestinal stromal tumors (GISTs) have emerged from being poorly defined, treatment-resistant tumors to a well-recognized, well-understood, and treatable tumor entity within only one decade. The understanding of GIST biology has made this tumor a paradigm for molecularly targeted therapy in solid tumors and provides informative insights into the advantages and limitations of so-called targeted therapeutics. Approximately 85% of GISTs harbor activating mutations in KIT or the homologous receptor tyrosine kinase PDGFRA gene. These mutations are an early event in GIST development and the oncoproteins serve as a target for the small molecule tyrosine kinase inhibitors imatinib and sunitinib. The existing and emerging treatment options demand exact morphologic classification and risk assessment. Although, KIT (CD117) immunohistochemistry is a reliable diagnostic tool in the diagnosis of GIST, KIT-negative GISTs, GISTs showing unusual morphology as well as GISTs which progress during or after treatment with imatinib/sunitinib can be a challenge for pathologists and clinicians. This review focuses on GIST pathogenesis, morphologic evaluation, promising new immunohistochemical markers, risk assessment, the role of molecular analysis, and the increasing problem of secondary imatinib resistance and its mechanisms.