Abstract
BackgroundGene fusions have been studied extensively, as frequent drivers of tumorigenesis as well as potential therapeutic targets. In many well-known cases, breakpoints occur at two intragenic positions, leading to in-frame gene-gene fusions that generate chimeric mRNAs. However, fusions often occur with intergenic breakpoints, and the role of such fusions has not been carefully examined.ResultsWe analyze whole-genome sequencing data from 268 patients to catalog gene-intergenic and intergenic-intergenic fusions and characterize their impact. First, we discover that, in contrast to the common assumption, chimeric oncogenic transcripts—such as those involving ETV4, ERG, RSPO3, and PIK3CA—can be generated by gene-intergenic fusions through splicing of the intervening region. Second, we find that over-expression of an upstream or downstream gene by a fusion-mediated repositioning of a regulatory sequence is much more common than previously suspected, with enhancers sometimes located megabases away. We detect a number of recurrent fusions, such as those involving ANO3, RGS9, FUT5, CHI3L1, OR1D4, and LIPG in breast; IGF2 in colon; ETV1 in prostate; and IGF2BP3 and SIX2 in thyroid cancers.ConclusionOur findings elucidate the potential oncogenic function of intergenic fusions and highlight the wide-ranging consequences of structural rearrangements in cancer genomes.
Highlights
Gene fusions have been studied extensively, as frequent drivers of tumorigenesis as well as potential therapeutic targets
Classification of fusion events We performed structural variations (SVs) analysis for 268 whole-genome sequencing (WGS) samples consisting of 40 breast invasive carcinomas (BRCA), 61 colon and rectum adenocarcinomas (COAD/READ), 47 thyroid carcinomas (THCA), and 120 prostate adenocarcinomas (PRAD), obtained from The Cancer Genome Atlas (TCGA) (Additional file 1: Fig. S1a and Additional file 2: Table S1)
To illustrate that even well-known chimeric oncogenic transcripts can be produced by gene-intergenic fusions, we show four such instances in Fig. 2: TMPRSS2-ETV4UIB (3 cases in PRAD), TMPRSS2-ERGUIB (1 case in PRAD), TBL1XR1-PIK3CA upstream intergenic breakpoint distances (UIB) (1 case in PRAD), and PTPRK-RSPO3UIB (2 cases in COAD/READ)
Summary
Gene fusions have been studied extensively, as frequent drivers of tumorigenesis as well as potential therapeutic targets. Among the examples are BCR-ABL1 in chronic myelogenous leukemia, for which the tyrosine kinase inhibitor imatinib works efficaciously [1], and TMPRSS-ERG in prostate cancer, present in nearly half of the prostate cases and is useful as a diagnostic tool [4]. In these fusions, breakpoints occur at two intragenic positions, resulting in in-frame gene-gene fusions that produce chimeric mRNAs [6]. Among all somatic rearrangements in the genome, the fraction of fusions with two intragenic breakpoints is small More common are those with one or two intergenic breakpoints, which we refer to as “gene-intergenic” and “intergenic-intergenic” fusions, respectively. The impact of such intergenic breakpoints on transcriptome has been unclear
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