Translocations in epithelial cancers

Abstract

Genomic translocations leading to the expression of chimeric transcripts characterize several hematologic, mesenchymal and epithelial malignancies. While several gene fusions have been linked to essential molecular events in hematologic malignancies, the identification and characterization of recurrent chimeric transcripts in epithelial cancers has been limited. However, the recent discovery of the recurrent gene fusions in prostate cancer has sparked a revitalization of the quest to identify novel rearrangements in epithelial malignancies. Here, the molecular mechanisms of gene fusions that drive several epithelial cancers and the recent technological advances that increase the speed and reliability of recurrent gene fusion discovery are explored.

Figure 1

Chronology of gene fusion discoveries in epithelial cancers.

Figure 2

Genomic structure of gene fusions with altered transcriptional regulation. The CTNNB1-PLAG1 and TMPRSS2-ERG chimeras represent an important class of gene fusions in which the proto-oncogene remains largely intact, but the genomic rearrangement places a new promoter and 5’-UTR upstream of the main coding sequence, leading to aberrant expression of the proto-oncogene.

Figure 3

HMGA2 gene fusions elude the Let-7 family of microRNAs. The HMGA2 mRNA structure is shown along with putative Let-7 family binding sequences in the HMGA2 3’-UTR. Results were predicted by TargetScan [202] and three representative microRNAs are shown with there highest probability binding sites of the seven total predicted sites along the 3’UTR. Distance to each predicted binding site is annotated as nucleotides from the start of the 3’UTR. Below the wild type HMGA2 mRNA are the HMGA2-FHIT and HMGA2-NFIB mRNAs that result from these two gene fusions. TargetScan did not predict any microRNA binding sites in these genes. As such, the HMGA2 gene fusions represent a second class of gene fusions in which the recombination event allows the proto-oncogene mRNA to evade microRNA-mediated silencing.

Figure 4

Nuclear retention of NUT. The BRD4-NUT gene fusion represents a third class of rearrangements in which the resulting protein gains activity to become a proto-oncogene. In this case, the two bromodomains of BRD4 are fused to NUT. Although NUT usually cycles between the nucleus and cytoplasm in a highly controlled manner, appendage of the BRD4 bromodomains to the majority of the NUT protein lead to nuclear retention of the protein and aberrant activity.

Figure 5

Difficulty in discovering gene fusions. One possibility is that a critical function of oncogenes in epithelial cancers is to alter genomic structure and it has been suggested that such changes could lead to cancer progression. However, if such a model were true, it would give a reason for the genomic heterogeneity observed in epithelial cancers that has allowed recurrent gene fusions to go unnoticed in solid tumors.