The impact of translocations and gene fusions on cancer causation

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Abstract
Chromosome aberrations are a characteristic feature of neoplasia, and acquired chromosome changes have now been reported in more than 50,000 cases across all main cancer types. Recurrent balanced chromosome rearrangements, in particular translocations, are strongly associated with distinct tumour entities, and there is compelling evidence that they represent an initial event in oncogenesis. Balanced chromosome abnormalities result in the formation of gene fusions and exert their tumorigenic action by two alternative mechanisms: overexpression of a gene in one of the breakpoints or the creation of a hybrid gene through the fusion of two genes, one in each breakpoint. A total of 358 gene fusions, involving 337 different genes, are known at present and have been described in all the main subtypes of human neoplasia. The prevalence of gene fusions varies considerably, from 0–100%, among different tumour types. Among malignant disorders, the proportions of gene fusion-positive cases are similar in haematological disorders, sarcomas and carcinomas. The gene fusions identified to date account for approximately 20% of human cancer morbidity. A number of conceptually important questions remain to be answered: why, how and when do chromosome aberrations originate? Are the resulting gene fusions sufficient for tumorigenesis, and if not, what is the pathogenetic relationship between these gene rearrangements and the other genetic and epigenetic alterations that characterize neoplastic cells?