Loss of NF2 defines a genetic subgroup of non-FOS-rearranged osteoblastoma.
Adolescent
Adult
Biomarkers, Tumor
/ genetics
Bone Neoplasms
/ genetics
Child
Child, Preschool
Enhancer Elements, Genetic
Epithelioid Cells
/ pathology
Europe
Female
Gene Deletion
Gene Rearrangement
Genetic Predisposition to Disease
Humans
Male
Middle Aged
Neurofibromin 2
/ genetics
Osteoblastoma
/ genetics
Osteogenesis
Phenotype
Proto-Oncogene Proteins c-fos
/ genetics
Wnt-5a Protein
/ genetics
Young Adult
FOS
FOSB
NF2
WNT5A
osteoblastoma
osteosarcoma
Journal
The journal of pathology. Clinical research
ISSN: 2056-4538
Titre abrégé: J Pathol Clin Res
Pays: England
ID NLM: 101658534
Informations de publication
Date de publication:
10 2020
10 2020
Historique:
received:
13
03
2020
revised:
05
05
2020
accepted:
11
05
2020
pubmed:
17
6
2020
medline:
14
10
2021
entrez:
17
6
2020
Statut:
ppublish
Résumé
Osteoblastoma is a locally aggressive tumour of bone. Until recently, its underlying genetic features were largely unknown. During the past two years, reports have demonstrated that acquired structural variations affect the transcription factor FOS in a high proportion of cases. These rearrangements modify the terminal exon of the gene and are believed to stabilise both the FOS transcript and the encoded protein, resulting in high expression levels. Here, we applied in-depth genetic analyses to a series of 29 osteoblastomas, including five classified as epithelioid osteoblastoma. We found recurrent homozygous deletions of the NF2 gene in three of the five epithelioid cases and in one conventional osteoblastoma. These events were mutually exclusive from FOS mutations. Structural variations were determined by deep whole genome sequencing and the number of FOS-rearranged cases was less than previously reported (10/23, 43%). One conventional osteoblastoma displayed a novel mechanism of FOS upregulation; bringing the entire FOS gene under the control of the WNT5A enhancer that is itself activated by FOS. Taken together, we show that NF2 loss characterises a subgroup of osteoblastomas, distinct from FOS-rearranged cases. Both NF2 and FOS are involved in regulating bone homeostasis, thereby providing a mechanistic link to the excessive bone growth of osteoblastoma.
Identifiants
pubmed: 32542935
doi: 10.1002/cjp2.172
pmc: PMC7578308
doi:
Substances chimiques
Biomarkers, Tumor
0
FOS protein, human
0
NF2 protein, human
0
Neurofibromin 2
0
Proto-Oncogene Proteins c-fos
0
WNT5A protein, human
0
Wnt-5a Protein
0
Types de publication
Journal Article
Multicenter Study
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
231-237Informations de copyright
© 2020 The Authors. The Journal of Pathology: Clinical Research published by The Pathological Society of Great Britain and Ireland & John Wiley & Sons, Ltd.
Références
Bioinformatics. 2012 Sep 15;28(18):i333-i339
pubmed: 22962449
Genome Biol. 2016 May 31;17(1):115
pubmed: 27246460
F1000Res. 2017 May 10;6:664
pubmed: 28781756
Am J Surg Pathol. 2019 Dec;43(12):1661-1667
pubmed: 31490237
J Biol Chem. 2017 Dec 29;292(52):21282-21290
pubmed: 29150442
Nat Commun. 2018 Jun 1;9(1):2150
pubmed: 29858576
PLoS Comput Biol. 2016 Apr 21;12(4):e1004873
pubmed: 27100738
Virchows Arch. 2020 Mar;476(3):455-463
pubmed: 31768625
Bioinformatics. 2013 Jan 1;29(1):15-21
pubmed: 23104886
Methods Mol Biol. 2019;1896:159-190
pubmed: 30474848
J Pathol. 2017 Apr;241(5):578-582
pubmed: 28139834
J Cell Physiol. 2018 Jun;233(6):4606-4617
pubmed: 29219182
Genes Chromosomes Cancer. 2019 Oct;58(10):731-736
pubmed: 31066955
Bioinformatics. 2014 Oct 15;30(20):2843-51
pubmed: 24974202
Wiley Interdiscip Rev Dev Biol. 2014 Nov-Dec;3(6):489-500
pubmed: 25270716
Nat Biotechnol. 2010 May;28(5):511-5
pubmed: 20436464
PLoS One. 2013 Nov 13;8(11):e80725
pubmed: 24236197
Cell Stem Cell. 2008 Aug 7;3(2):221-7
pubmed: 18682243