Abstract
Ewing sarcoma (ES) is an aggressive sarcoma, and is the second most common bone sarcoma in childhood. Disease specific t(11;22)(~85–90%), t(21;22)(~5–10%), or rarer variant translocations with the involvement of chromosome 22 (~5%) are present. At the gene level, the EWSR1 gene fuses with FLI1, ERG or other ETS transcription factor family members. So far, no ES has been identified with a fusion to transcription factors other than ETS.
By using a panel of molecular tools such as multicolor FISH and array-CGH, a ring chromosome containing chromosomes 20 and 22 was identified in four ES cases. Molecular karyotyping showed the translocation and amplification of regions of chromosomes 20q13 and 22q12. Cloning of the breakpoint showed an in-frame fusion between the EWSR1 and NFATc2 genes. The translocation led to the loss of the N-terminal, calcineurin-dependent control region. Consequently, the remaining intact DNA binding domain of NFATc2 is under control of the EWSR1 promoter region permitting oncogenic activation. Intriguingly, in all cases a distinct histological feature was observed.
In conclusion: a new translocation involving EWS and NFATc2 was cloned that is associated with a histological variant of ES. The NFATc2 transcription factor is not a member of the ETS family of transcription factors. NFTAC2 has well characterized functions in T-cell differentiation and immune response. For the first time a direct involvement of NFATc2 in oncogenesis has been shown.
Correspondence should be addressed to Professor Stefan Bielack, Olgahospital, Klinikum Stuttgart, Bismarkstrasse 8, D-70176 Stuttgart, Germany. Email: s.bielack@klinikum_stuttgart.de
