Fig. 2.

Examples of events that generate gene-intergenic fusions with chimeric mRNAs. a In the TMPRSS2-ETV4^UIB fusion, the breakpoint in TMPRSS2 occurs in its first intron; the other breakpoint occurs in the upstream intergenic region of ETV4 by inter-chromosomal translocation. At the mRNA level, the first exon of TMPRSS2 is fused with the second exon of ETV4 (left), with the skipping of the first ETV4 exon. The right panel shows the greatly elevated ETV4 expression levels of the three TMPRSS2-ETV4^UIB fusion-positive cases with verified chimeric mRNA (red) compared to other prostate cancer cases (black). In TCGA-HC-7079 (orange dot), the TMPRSS2-ETV4 chimeric mRNA was identified in RNA-seq, but the exact breakpoints were not identified in WGS due to the low coverage (~ 4–8×) of prostate cases. b In the TMPRSS2-ERG^UIB fusion, the breakpoints are similarly distributed but caused by a deletion to generate fusion transcripts with the first exon of TMPRSS2 fused with the second exon of ERG. The right panel shows that this case of TMPRSS2-ERG^UIB showed elevated expression of ERG (red), comparable to the in-frame gene-gene fusion cases of TMPRSS2-ERG (green) and SLC45A3-ERG (blue). Similar to a, orange dots indicate cases with TMPRSS-ERG chimeric mRNAs detected in RNA-seq but not in WGS due to the low coverage of this particular tumor type. c In one case of TBL1XR1-PIK3CA occurring in a prostate sample, the first exon of TBL1XR1 is fused to the second exon of PIK3CA by inversion. In this case, the TBL1XR1 exon is in the 5′ UTR, and the protein is not chimeric. The other case of TBL1XR1-PIK3CA is a gene-gene fusion in BRCA. Both cases showed much greater expression levels of PIK3CA. d An inversion generates the PTPRK-RSPO3^UIB fusion, similar to c, with the three fusion cases showing markedly increased RSPO3 expression. e Gene-intergenic (gene-gene^UIB) fusion could produce two different scenarios. In the first scenario (left), the exon before the breakpoint in the upstream gene (GENE-A) and the second exon of the downstream gene (GENE-B) are fused, with the skipping of the first exon of GENE-B due to a lack of splicing signal. The breakpoint typically occurs after the first exon (marked with “*”), but it could occur elsewhere, too. In the second scenario, repositioned regulatory units (e.g., promoters, enhancers, or repressors) result in up- or downregulation of the downstream gene