IDH Mutation Analysis in Ewing Sarcoma Family Tumors

Ewing sarcoma (ES) is the second most common primary bone sarcoma of those that typically develop in children and young adults. It is also called ES family tumor (ESFT) and includes extraskeletal ES and primitive neuroectodermal tumor [1]. ESFT is an aggressive tumor with metastases present at diagnosis in 20%–25% of cases. With current therapeutic options, the 5-year survival rate for non-metastatic disease is as high as 70%. However, survival for patients who have metastasis is approximately 20%, and for those who develop relapsed or refractory disease, the survival rate is less than 10%. There is a need to identify alternative therapeutic agents that appropriately target the biomolecular mechanisms of this disease [1]. There is a group of tumors and tumor syndromes that carry mutations in metabolic enzymes involved in the tricarboxylic acid cycle, especially enzymes in the isocitrate dehydrogenase (IDH) family. IDH catalyzes the oxidative decarboxylation of isocitrate to yield α-ketoglutarate (α-KG) with production of reduced nicotinamide adenine dinucleotide (NADH). Dysfunctional IDH leads to reduced production of α-KG and NADH and increased production of 2-hydroxyglutarate, an oncometabolite. Together, this results in increased oxidative damage and stabilization of hypoxia-inducible factor α, causing cells to be prone to tumorigenesis [2]. A functional study proved that IDH2 mutations in mesenchymal cells can induce malignant transformation [3]. Mutations in IDH1 are reported to cluster at a single hotspot locus (R132), whereas IDH2 mutations occur primarily at two loci (R140 and R172) [2]. Recurrent somatic IDH1/2 mutations have been described in gliomas and secondary glioblastomas [4]. Similar IDH1/2 mutations have been detected in acute myeloid leukemia [5] and myelodysplastic disorders [6]. Recently, IDH mutations have been reported in a large proportion of cartilaginous tumors [7], a small number of osteosarcomas [8], and in giant cell tumors [9]. The fact that these mutations appear to be present in these relatively common bone tumors led us to investigate IDH1/2 mutations in ESFTs.