Dysregulation of cancer genes by recurrent intergenic fusions

Background 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 oc...

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Bibliographic Details
Published in:Genome Biology 2020-07, Vol.21 (1), p.1-166, Article 166
Main Authors: Yun, Jae Won, Yang, Lixing, Park, Hye-Young, Lee, Chang-Woo, Cha, Hongui, Shin, Hyun-Tae, Noh, Ka-Won, Choi, Yoon-La, Park, Woong-Yang, Park, Peter J.
Format: Article
Language:English
Subjects:
Algorithms
Breakpoints
Breast
Chimeric transcripts
Colon
Consortia
Deoxyribonucleic acid
DNA
Enhancer hijacking
Enhancers
Genes
Genomes
Insulin-like growth factor II
Kinases
Leukemia
Overexpression
Prostate
Prostate cancer
Regulatory sequences
SIX gene family
Splicing
Structural variations
Therapeutic applications
Thyroid
Thyroid gland
Tumorigenesis
Whole genome sequencing
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Summary:Background 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. Results 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. Conclusion Our findings elucidate the potential oncogenic function of intergenic fusions and highlight the wide-ranging consequences of structural rearrangements in cancer genomes.
ISSN:1474-760X
1474-7596
1474-760X
DOI:10.1186/s13059-020-02076-2