Identification of recurrent FHL2-GLI2 oncogenic fusion in sclerosing stromal tumors of the ovary.
Adolescent
Adult
Female
Gene Dosage
Gene Expression Regulation, Neoplastic
Hedgehog Proteins
/ genetics
Humans
LIM-Homeodomain Proteins
/ genetics
Middle Aged
Muscle Proteins
/ genetics
Mutation
Nuclear Proteins
/ genetics
Oncogene Proteins, Fusion
/ genetics
Ovarian Neoplasms
/ genetics
Sclerosis
Sex Cord-Gonadal Stromal Tumors
/ genetics
Stromal Cells
/ pathology
Transcription Factors
/ genetics
Exome Sequencing
Young Adult
Zinc Finger Protein Gli2
/ genetics
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
02 01 2020
02 01 2020
Historique:
received:
15
05
2019
accepted:
26
11
2019
entrez:
4
1
2020
pubmed:
4
1
2020
medline:
14
4
2020
Statut:
epublish
Résumé
Sclerosing stromal tumor (SST) of the ovary is a rare type of sex cord-stromal tumor (SCST), whose genetic underpinning is currently unknown. Here, using whole-exome, targeted capture and RNA-sequencing, we report recurrent FHL2-GLI2 fusion genes in 65% (17/26) of SSTs and other GLI2 rearrangements in additional 15% (4/26) SSTs, none of which are detected in other types of SCSTs (n = 48) or common cancer types (n = 9,950). The FHL2-GLI2 fusions result in transcriptomic activation of the Sonic Hedgehog (SHH) pathway in SSTs. Expression of the FHL2-GLI2 fusion in vitro leads to the acquisition of phenotypic characteristics of SSTs, increased proliferation, migration and colony formation, and SHH pathway activation. Targeted inhibition of the SHH pathway results in reversal of these oncogenic properties, indicating its role in the pathogenesis of SSTs. Our results demonstrate that the FHL2-GLI2 fusion is likely the oncogenic driver of SSTs, defining a genotypic-phenotypic correlation in ovarian neoplasms.
Identifiants
pubmed: 31896750
doi: 10.1038/s41467-019-13806-x
pii: 10.1038/s41467-019-13806-x
pmc: PMC6940380
doi:
Substances chimiques
FHL2 protein, human
0
GLI2 protein, human
0
Hedgehog Proteins
0
LIM-Homeodomain Proteins
0
Muscle Proteins
0
Nuclear Proteins
0
Oncogene Proteins, Fusion
0
SHH protein, human
0
Transcription Factors
0
Zinc Finger Protein Gli2
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
44Subventions
Organisme : NCI NIH HHS
ID : K12 CA184746
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA008748
Pays : United States
Références
Nat Commun. 2018 Aug 30;9(1):3533
pubmed: 30166553
Nat Biotechnol. 2012 May;30(5):413-21
pubmed: 22544022
Am J Surg Pathol. 2011 Apr;35(4):484-94
pubmed: 21378549
Front Genet. 2019 Jun 12;10:556
pubmed: 31244888
Bioinformatics. 2013 Oct 15;29(20):2539-46
pubmed: 23956304
Nat Med. 2017 Apr;23(4):483-492
pubmed: 28263309
Proc Natl Acad Sci U S A. 2015 May 19;112(20):6383-8
pubmed: 25941387
Mod Pathol. 2015 Dec;28(12):1603-12
pubmed: 26428316
J Pathol. 2016 Jul;239(3):335-43
pubmed: 27101025
Semin Diagn Pathol. 2014 Sep;31(5):382-426
pubmed: 25440719
Nucleic Acids Res. 2016 Sep 19;44(16):e131
pubmed: 27270079
Nucleic Acids Res. 2016 Nov 16;44(20):e151
pubmed: 27471031
Hum Mol Genet. 2005 Aug 1;14(15):2181-8
pubmed: 15994174
Genome Res. 2016 Jan;26(1):108-18
pubmed: 26556708
Nucleic Acids Res. 2012 May;40(10):4288-97
pubmed: 22287627
Cancer. 1973 Mar;31(3):664-70
pubmed: 4348335
Nucleic Acids Res. 2018 Jan 4;46(D1):D1144-D1149
pubmed: 29099951
Cell Rep. 2019 Jun 4;27(10):3006-3018.e4
pubmed: 31167144
Mod Pathol. 2017 Oct;30(10):1443-1452
pubmed: 28731043
Nat Rev Cancer. 2008 Oct;8(10):743-54
pubmed: 18813320
Nature. 2011 Jun 29;474(7353):609-15
pubmed: 21720365
Case Rep Pathol. 2012;2012:592836
pubmed: 23097733
Cancers (Basel). 2016 Feb 15;8(2):
pubmed: 26891329
Pathology. 2018 Jan;50(1):5-15
pubmed: 29132723
Nature. 2012 Oct 4;490(7418):61-70
pubmed: 23000897
Nature. 1998 Jan 1;391(6662):90-2
pubmed: 9422511
Nat Genet. 2014 Nov;46(11):1166-9
pubmed: 25240283
J Obstet Gynaecol Res. 2005 Oct;31(5):432-5
pubmed: 16176513
Histopathology. 2013 Jan;62(1):71-88
pubmed: 23240671
Development. 1999 Sep;126(17):3915-24
pubmed: 10433919
Annu Rev Cell Dev Biol. 2011;27:513-37
pubmed: 21801010
Cell. 2013 Aug 15;154(4):801-13
pubmed: 23953112
Histopathology. 2016 Jan;68(2):262-71
pubmed: 25951887
Behav Brain Res. 2001 Nov 1;125(1-2):279-84
pubmed: 11682119
Int J Gynecol Pathol. 2001 Oct;20(4):346-52
pubmed: 11603218
Bioinformatics. 2007 Nov 1;23(21):2881-7
pubmed: 17881408
J Cell Mol Med. 2018 Mar;22(3):1684-1695
pubmed: 29193729
Genes Chromosomes Cancer. 2014 Oct;53(10):845-56
pubmed: 24942367
Eur J Cancer. 2006 Mar;42(4):437-45
pubmed: 16406505
Proc Natl Acad Sci U S A. 2009 Nov 3;106(44):18740-4
pubmed: 19841262
Am J Pathol. 2004 May;164(5):1645-53
pubmed: 15111311
Genome Biol. 2011;12(1):R6
pubmed: 21247443
Bioinformatics. 2010 Jan 1;26(1):139-40
pubmed: 19910308
Dev Cell. 2016 Aug 22;38(4):333-44
pubmed: 27554855
Nature. 2009 Nov 5;462(7269):108-12
pubmed: 19847166
Endocr Rev. 2018 Feb 1;39(1):1-20
pubmed: 29028960
Nat Rev Cancer. 2015 Jun;15(6):371-81
pubmed: 25998716
N Engl J Med. 2012 Jan 19;366(3):234-42
pubmed: 22187960
J Natl Cancer Inst. 2019 Jul 1;111(7):737-741
pubmed: 30649385
Gynecol Oncol. 2018 May;149(2):420-427
pubmed: 29458976
Cell. 2017 Feb 9;168(4):584-599
pubmed: 28187282
EMBO J. 2015 Jan 13;34(2):200-17
pubmed: 25476449
Endocrinology. 2005 Aug;146(8):3558-66
pubmed: 15878962
N Engl J Med. 2009 Jun 25;360(26):2719-29
pubmed: 19516027
Cancer Res. 1997 Mar 1;57(5):842-5
pubmed: 9041183
J Mol Diagn. 2012 Jan;14(1):22-9
pubmed: 22166544
Nat Commun. 2018 May 8;9(1):1816
pubmed: 29739933
Int J Gynecol Pathol. 2015 Jul;34(4):357-62
pubmed: 25851706
Mod Pathol. 2020 Mar;33(3):456-467
pubmed: 31383964
J Pathol. 2015 Oct;237(2):179-89
pubmed: 26095796
Mol Endocrinol. 2012 Aug;26(8):1278-90
pubmed: 22734036
Proc Natl Acad Sci U S A. 2018 Mar 27;115(13):3392-3397
pubmed: 29531057
Cancer Discov. 2018 Feb;8(2):174-183
pubmed: 29247016
Biochim Biophys Acta. 2002 Aug 19;1577(1):93-101
pubmed: 12151099
Am J Surg Pathol. 2002 Nov;26(11):1477-83
pubmed: 12409724
Oncogene. 2011 Jul 21;30(29):3222-33
pubmed: 21358673
J Pathol. 2018 Feb;244(2):143-150
pubmed: 29149504
J Mol Diagn. 2015 May;17(3):251-64
pubmed: 25801821
PLoS Comput Biol. 2011 May;7(5):e1001138
pubmed: 21625565