Cementoblastomas are rare odontogenic tumors developing in close proximity to the roots of teeth. Due to their striking morphologic resemblance to osteoblastomas of the peripheral skeleton, we set... Show moreCementoblastomas are rare odontogenic tumors developing in close proximity to the roots of teeth. Due to their striking morphologic resemblance to osteoblastomas of the peripheral skeleton, we set out to determine whether cementoblastomas harbor the same FOS rearrangements with overexpression of c-FOS as has recently been described for osteoblastomas. In total, 16 cementoblastomas were analyzed for FOS expression by immunohistochemistry and for FOS rearrangements by fluorescence in situ hybridization (FISH). We observed strong and diffuse staining of c-FOS in 71% of cementoblastomas and identified a FOS rearrangement in all cases (n=3) applicable for FISH. In the remaining cases, FISH failed due to decalcification. Cementoblastomas harbor similar FOS rearrangements and show overexpression of c-FOS like osteoblastomas, suggesting that both entities might represent parts of the spectrum of the same disease. Show less
Saba, K.H.; Cornmark, L.; Hofvander, J.; Magnusson, L.; Nilsson, J.; Bos, H. van den; ... ; Nord, K.H. 2020
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... Show moreOsteoblastoma 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. Show less
Osteoid osteoma and osteoblastoma are bone-forming tumors shown to harbor FOS (87%) and FOSB (3%) rearrangements. The aim was to evaluate the immunohistochemical expression of FOS and FOSB in these... Show moreOsteoid osteoma and osteoblastoma are bone-forming tumors shown to harbor FOS (87%) and FOSB (3%) rearrangements. The aim was to evaluate the immunohistochemical expression of FOS and FOSB in these tumors in comparison to other bone tumors, to evaluate the influence of decalcification, and to correlate immunohistochemical findings with the underlying genetic alteration using fluorescence in situ hybridization (FISH). Immunohistochemistry using whole sections was performed on osteoid osteoma (n=23), osteoblastoma (n=22), osteoblastoma-like osteosarcoma (n=3), reactive (n=3), and proliferative (n=11) bone lesions. Immunoreactivity in giant cell tumor of bone (n=74), aneurysmal bone cyst (n=6), chondromyxoid fibroma (n=20), osteosarcoma (n=85), chondroblastoma (n=17), and clear cell chondrosarcoma (n=20) was assessed using tissue micro arrays. Strong nuclear expression of FOS in > 50% of the tumor cells was observed in all osteoid osteomas (22/22), in 57% of osteoblastomas (12/21) and in 3/197 control cases. FOS immunoreactivity disappeared after > 3 days decalcification. FOS rearrangements were present in 94% of osteoid osteomas and osteoblastomas, with a concordance of 86% between FISH and immunohistochemistry. Two osteoblastomas (5%) were positive for FOSB, as opposed to 8/177 control cases. Additional FISH revealed no FOSB rearrangements in these cases. To conclude, in short decalcified biopsies, FOS immunohistochemistry can be used to diagnose osteoid osteoma and osteoblastoma, as overexpression is seen in the majority, being rare in their mimics. FOS immunohistochemistry should not be used after long decalcification. Moreover, low level of focal expression found in other lesions and tissues might cause diagnostic problems, in which case FISH could be employed. Show less
Bone tumours are difficult to diagnose and treat, as they are rare and over 60 different subtypes are recognised. The emergence of next-generation sequencing has partly elucidated the molecular... Show moreBone tumours are difficult to diagnose and treat, as they are rare and over 60 different subtypes are recognised. The emergence of next-generation sequencing has partly elucidated the molecular mechanisms behind these tumours, including the group of bone forming tumours (osteoma, osteoid osteoma, osteoblastoma and osteosarcoma). Increased knowledge on the molecular mechanism could help to identify novel diagnostic markers and/or treatment options. Osteoid osteoma and osteoblastoma are bone forming tumours without malignant potential that have overlapping morphology. They were recently shown to carry FOS and-to a lesser extent-FOSB rearrangements suggesting that these tumours are closely related. The presence of these rearrangements could help discriminate these entities from other lesions with woven bone deposition. Osteosarcoma is a malignant bone forming tumour for which different histological subtypes are recognised. High-grade osteosarcoma is the prototype of a complex karyotype tumour, and extensive research exploring its molecular background has identified phenomena like chromothripsis and kataegis and some recurrent alterations. Due to lack of specificity, this has not led to a valuable novel diagnostic marker so far. Nevertheless, these studies have also pointed towards potential targetable drivers of which the therapeutic merit remains to be further explored. Show less