biostudies-literatureYun JWKorea Health Industry Development InstituteNational Research Foundation166https://www.ebi.ac.uk/biostudies/studies/S-EPMC7339451biostudies-literatureUnknown21(1)<h4>Background</h4>Gene 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.<h4>Results</h4>We 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.<h4>Conclusion</h4>Our findings elucidate the potential oncogenic function of intergenic fusions and highlight the wide-ranging consequences of structural rearrangements in cancer genomes.Genome biologyDysregulation of cancer genes by recurrent intergenic fusions.PMC7339451HI15C3224NRF-2016H1A2A1907938HI13C2096Noh KWPark PJChoi YLYang LCha HLee CWShin HTPark HYPark WYYun JWfalseDysregulation of cancer genes by recurrent intergenic fusions.<h4>Background</h4>Gene 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.<h4>Results</h4>We 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.<h4>Conclusion</h4>Our findings elucidate the potential oncogenic function of intergenic fusions and highlight the wide-ranging consequences of structural rearrangements in cancer genomes.2020-01-01T00:00:00Z2020 Jul2025-04-26T08:08:46.67Z2025-04-06T12:38:50.435ZS-EPMC73394513263139110.1186/s13059-020-02076-2