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Loss of NF2 defines a genetic subgroup of non-FOS-rearranged osteoblastoma

Saba, Karim H. LU ; Cornmark, Louise LU ; Hofvander, Jakob LU ; Magnusson, Linda LU ; Nilsson, Jenny LU ; van den Bos, Hilda ; Spierings, Diana C.J. ; Foijer, Floris ; Staaf, Johan LU and Brosjö, Otte , et al. (2020) In Journal of Pathology: Clinical Research 6(4). p.231-237
Abstract

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... (More)

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.

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organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
FOS, FOSB, NF2, osteoblastoma, osteosarcoma, WNT5A
in
Journal of Pathology: Clinical Research
volume
6
issue
4
pages
7 pages
publisher
Wiley-Blackwell
external identifiers
  • scopus:85086441659
  • pmid:32542935
ISSN
2056-4538
DOI
10.1002/cjp2.172
language
English
LU publication?
yes
id
2be22c0d-de83-44be-a5df-295450a26d06
date added to LUP
2020-07-03 12:46:06
date last changed
2021-02-17 04:46:13
@article{2be22c0d-de83-44be-a5df-295450a26d06,
  abstract     = {<p>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.</p>},
  author       = {Saba, Karim H. and Cornmark, Louise and Hofvander, Jakob and Magnusson, Linda and Nilsson, Jenny and van den Bos, Hilda and Spierings, Diana C.J. and Foijer, Floris and Staaf, Johan and Brosjö, Otte and Sumathi, Vaiyapuri P. and Lam, Suk Wai and Szuhai, Karoly and Bovée, Judith V.M.G. and Kovac, Michal and Baumhoer, Daniel and Styring, Emelie and Nord, Karolin H.},
  issn         = {2056-4538},
  language     = {eng},
  number       = {4},
  pages        = {231--237},
  publisher    = {Wiley-Blackwell},
  series       = {Journal of Pathology: Clinical Research},
  title        = {Loss of NF2 defines a genetic subgroup of non-FOS-rearranged osteoblastoma},
  url          = {http://dx.doi.org/10.1002/cjp2.172},
  doi          = {10.1002/cjp2.172},
  volume       = {6},
  year         = {2020},
}