Fusion oncogenes—genetic musical chairs
A partir de 124 échantillons de tumeurs primitives prélevés sur des patients atteints d'un sarcome d'Ewing, cette étude met notamment en évidence un mécanisme appelé "chromoplexie" qui, dans près de la moitié des tumeurs, induit la fusion des gènes EWSR1 et ETS
The cytogenetic definitions of many cancers predate the genome sequencing era. Indeed, some classes of cancers (largely subtypes of sarcomas, lymphomas, and leukemias) have long been defined by simple and distinct patterns of chromosomal changes, or karyotypes, that, in many cases, feature a single pathognomonic somatic translocation of two genomic regions that creates a fusion oncogene (for example, the Philadelphia chromosome translocation in chronic myelogenous leukemia results in the BCR-ABL1 fusion oncogene) (1). Whereas many common cancers display genomic complexity consistent with multistep oncogenesis, such as carcinomas of breast and lung, cancers that are defined by translocations typically display simple karyotypes, suggesting that they were shaped by a single translocation. However, the cytogenetic simplicity of these cancers may mask more complex genomic events. On page 891 of this issue, Anderson et al. (2) report whole-genome sequencing (WGS) of 50 Ewing sarcomas (EWSs), an aggressive sarcoma that is defined by fusion between the EWS RNA binding protein 1 (EWSR1) gene on chromosome 22 and an E26 transformation-specific (ETS) family transcription factor gene, either FLI1 at 11q24 or ERG at 21q11 (3). Anderson et al. show that ∼40% of EWSR1-FLI1 fusions and all EWSR1-ERG fusions arise via a complex rearrangement pattern called chromoplexy, which was first identified in prostate cancer (4). They suggest that chromoplexy “bursts” may be early initiating events in Ewing sarcomagenesis and mark a more aggressive form of the disease.