Journal
JOURNAL OF PATHOLOGY CLINICAL RESEARCH
Volume 6, Issue 4, Pages 231-237Publisher
WILEY
DOI: 10.1002/cjp2.172
Keywords
FOS; FOSB; NF2; WNT5A; osteoblastoma; osteosarcoma
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Funding
- Royal Physiographic Society (Lund, Sweden)
- Faculty of Medicine at Lund University
- Swedish Childhood Cancer Fund
- Swedish Cancer Society
- Swedish Research Council
- Ake Wiberg Foundation
- Crafoord Foundation
- Maggie Stephens Foundation
- Erik and Angelica Sparres Research Foundation
- Greta and Johan Kocks Foundation
- Swedish Government [F 2014/413]
- Swiss National Science Foundation
- Foundation of the Basel Bone Tumour Reference Centre
- Gertrude von Meissner Stiftung
- Stiftung fur krebskranke Kinder, Regio Basiliensis
- Netherlands Organization for Scientific Research [ZON-MV VICI 170.055]
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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 factorFOSin a high proportion of cases. These rearrangements modify the terminal exon of the gene and are believed to stabilise both theFOStranscript 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 theNF2gene in three of the five epithelioid cases and in one conventional osteoblastoma. These events were mutually exclusive fromFOSmutations. Structural variations were determined by deep whole genome sequencing and the number ofFOS-rearranged cases was less than previously reported (10/23, 43%). One conventional osteoblastoma displayed a novel mechanism of FOS upregulation; bringing the entireFOSgene under the control of theWNT5Aenhancer that is itself activated by FOS. Taken together, we show thatNF2loss characterises a subgroup of osteoblastomas, distinct fromFOS-rearranged cases. BothNF2andFOSare involved in regulating bone homeostasis, thereby providing a mechanistic link to the excessive bone growth of osteoblastoma.
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