Abstract
Fusion RNAs are a hallmark of some cancers. They result either from chromosomal rearrangements or from splicing mechanisms that are non-chromosomal rearrangements. Chromosomal rearrangements that result in gene fusions are particularly prevalent in sarcomas and hematopoietic malignancies; they are also common in solid tumors. The splicing process can also give rise to more complex RNA patterns in cells. Gene fusions frequently affect tyrosine kinases, chromatin regulators, or transcription factors, and can cause constitutive activation, enhancement of downstream signaling, and tumor development, as major drivers of oncogenesis. In addition, some fusion RNAs have been shown to function as noncoding RNAs and to affect cancer progression. Fusion genes and RNAs will therefore become increasingly important as diagnostic and therapeutic targets for cancer development. Here, we discuss the function, biogenesis, detection, clinical relevance, and therapeutic implications of oncogenic fusion genes and RNAs in cancer development. Further understanding the molecular mechanisms that regulate how fusion RNAs form in cancers is critical to the development of therapeutic strategies against tumorigenesis.
Highlights
Cancer is a disease of the genome [1,2]
The abnormally small resulting chromosome, named the Philadelphia chromosome, was found in over 95% of patients with chronic myelogenous leukemia (CML) and consisted of the breakpoint cluster region (BCR) gene fused to the second exon of the Abelson murine leukemia viral oncogene homolog 1 (ABL1) gene [8,9]
Additional examples of cancer-associated chromosomal aberrations have been identified in other hematological malignancies and sarcomas; for example, mixed lineage leukemia (MLL) fusions, RUNX1–RUNX1T1 and PML–RARα, EWSR1–FLI1 and EVT6–NTRK3 [10,11]
Summary
Cancer is a disease of the genome [1,2]. Gene fusions or chromosomal rearrangements are an important class of somatic alterations in cancer and can have important roles in the initial steps of tumorigenesis. [3,4,5]. Gene fusions or chromosomal rearrangements are an important class of somatic alterations in cancer and can have important roles in the initial steps of tumorigenesis. Fusion circRNAs (f-circRNAs) that are generated by chromosome rearrangement contribute to oncogenic roles [35]. Targeting oncogenic fusion genes and RNAs specific to cancer tissue for treatment and diagnosis could bring us closer to the approach. These fusions are often present at clonal levels within tumors; their generation is frequently the founding genetic abnormality that drives the cancer [37,38]. Development of therapeutic strategies that target fusion genes and RNAs, and the study of their mechanisms of production and actions, may provide robust opportunities to eradicate cancers that harbor aberrant genes and RNAs
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