Dysregulation of cancer genes by recurrent intergenic fusions.
Chimeric transcripts
Enhancer hijacking
Structural variations
Whole-genome sequencing
Journal
Genome biology
ISSN: 1474-760X
Titre abrégé: Genome Biol
Pays: England
ID NLM: 100960660
Informations de publication
Date de publication:
06 07 2020
06 07 2020
Historique:
received:
13
04
2020
accepted:
16
06
2020
entrez:
8
7
2020
pubmed:
8
7
2020
medline:
8
7
2021
Statut:
epublish
Résumé
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. 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. Our findings elucidate the potential oncogenic function of intergenic fusions and highlight the wide-ranging consequences of structural rearrangements in cancer genomes.
Sections du résumé
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.
Identifiants
pubmed: 32631391
doi: 10.1186/s13059-020-02076-2
pii: 10.1186/s13059-020-02076-2
pmc: PMC7339451
doi:
Substances chimiques
DNA, Intergenic
0
Homeodomain Proteins
0
IGF2BP3 protein, human
0
Nerve Tissue Proteins
0
RNA-Binding Proteins
0
SIX2 protein, human
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
166Références
Trends Cancer. 2016 Sep;2(9):475-484
pubmed: 28210711
Nat Methods. 2009 Sep;6(9):677-81
pubmed: 19668202
Nature. 2012 Aug 30;488(7413):660-4
pubmed: 22895193
Genome Biol. 2016 Dec 16;17(1):261
pubmed: 27986087
Int J Exp Pathol. 2013 Jun;94(3):203-11
pubmed: 23594372
Clin Cancer Res. 2008 Jul 1;14(13):4275-83
pubmed: 18594010
Cancer Res. 2006 Apr 1;66(7):3396-400
pubmed: 16585160
Cell. 2014 Apr 10;157(2):369-381
pubmed: 24703711
Oncogene. 2003 Sep 4;22(38):6111-4
pubmed: 12955091
Breast Cancer Res Treat. 2003 Jul;80(1):15-21
pubmed: 12889595
Semin Cancer Biol. 2014 Dec;29:3-12
pubmed: 25068994
Cell Rep. 2018 Apr 3;23(1):227-238.e3
pubmed: 29617662
Cell. 2014 Oct 23;159(3):676-90
pubmed: 25417114
Cell. 2014 Dec 18;159(7):1665-80
pubmed: 25497547
Bioinformatics. 2011 Oct 15;27(20):2903-4
pubmed: 21840877
Oncogene. 2001 Sep 10;20(40):5580-94
pubmed: 11607811
Nat Commun. 2020 Feb 5;11(1):736
pubmed: 32024823
Theranostics. 2017 Feb 27;7(5):1114-1132
pubmed: 28435452
BMC Clin Pathol. 2011 Nov 04;11:13
pubmed: 22050638
Cancer Cell. 2014 Sep 8;26(3):319-330
pubmed: 25155756
Nucleic Acids Res. 2011 Jan;39(Database issue):D712-7
pubmed: 21071422
Cancer Res. 2014 Dec 15;74(24):7357-70
pubmed: 25348955
Proc Natl Acad Sci U S A. 2016 Nov 29;113(48):13768-13773
pubmed: 27856756
J Clin Pathol. 2015 Jul;68(7):506-10
pubmed: 25750267
Neoplasia. 2013 Jul;15(7):720-6
pubmed: 23814484
Bioinformatics. 2016 Sep 15;32(18):2847-9
pubmed: 27207943
Nature. 2012 Sep 6;489(7414):57-74
pubmed: 22955616
Biochim Biophys Acta. 2011 Dec;1810(12):1141-9
pubmed: 21978830
Cell Rep. 2018 Jul 10;24(2):515-527
pubmed: 29996110
Mol Oncol. 2015 Apr;9(4):861-76
pubmed: 25655580
Cell. 2013 May 9;153(4):919-29
pubmed: 23663786
Proc Natl Acad Sci U S A. 2005 Oct 25;102(43):15545-50
pubmed: 16199517
Nat Rev Cancer. 2015 Jun;15(6):371-81
pubmed: 25998716
Tumour Biol. 2014 Jan;35(1):277-86
pubmed: 23918300
Nat Commun. 2014 Sep 10;5:4846
pubmed: 25204415
Cell Syst. 2016 Nov 23;3(5):496-499.e2
pubmed: 27863956
Nat Commun. 2016 Apr 05;7:11199
pubmed: 27045898
Cell Prolif. 2019 Jul;52(4):e12617
pubmed: 31012173
Proc Natl Acad Sci U S A. 2017 Feb 28;114(9):2307-2312
pubmed: 28193878
Nat Biotechnol. 2011 Jan;29(1):24-6
pubmed: 21221095
Cell Death Dis. 2017 Aug 3;8(8):e2968
pubmed: 28771224
Nature. 2012 Jul 18;487(7407):330-7
pubmed: 22810696
Nat Commun. 2013;4:2185
pubmed: 23887589
Nature. 2016 Jan 7;529(7584):97-100
pubmed: 26700806
Nucleic Acids Res. 2010 Oct;38(18):e178
pubmed: 20802226
Science. 2005 Oct 28;310(5748):644-8
pubmed: 16254181
Clin Cancer Res. 2005 May 1;11(9):3326-34
pubmed: 15867231
Br J Cancer. 1999 Mar;79(9-10):1494-9
pubmed: 10188896
N Engl J Med. 2001 Apr 5;344(14):1031-7
pubmed: 11287972
Am J Hum Genet. 2016 May 5;98(5):843-856
pubmed: 27153396
Oncogene. 2015 Sep 10;34(37):4845-54
pubmed: 25500544
PLoS Comput Biol. 2011 May;7(5):e1001138
pubmed: 21625565