An update of molecular pathology of bone tumors. Lessons learned from investigating samples by next generation sequencing

Baumhoer, Daniel; Amary, Fernanda; Flanagan, Adrienne M.

doi:10.1002/gcc.22699

Cited by 70 publications

(58 citation statements)

References 90 publications

(194 reference statements)

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“…However, depending on the developmental timing of the derivation of a bone cancer from the mesenchymal lineage during embryonal or adult osteogenesis, these roles may vary. Chordoma localized along the skeletal axis in bones from the skull base to the coccyx is considered to derive from early developmental mesodermal cell types in notochord remnants [164]. Chondrosarcoma, the most common malignant bone tumor in adults, is considered to derive from benign enchondroma or osteochondroma, which are thought to arise from rests of growth plate cartilage or chondrocytes [165].…”

Section: Yap and Taz As Regulators Of Osteogenesismentioning

confidence: 99%

“…For osteosarcoma, there is evidence for derivation from pre-osteoblasts or osteoblasts with the contribution of microenvironmental mesenchymal stem cells (MSC) (for review, [173,174]). Similarly, a giant cell tumor of bone, a rare, locally aggressive tumor which occasionally metastasizes to the lung, is of osteoblastic lineage [164].…”

Section: Yap and Taz As Regulators Of Osteogenesismentioning

confidence: 99%

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The YAP/TAZ Pathway in Osteogenesis and Bone Sarcoma Pathogenesis

Kovar

Bierbaumer

Radic-Sarikas

2020

Cells

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YAP and TAZ are intracellular messengers communicating multiple interacting extracellular biophysical and biochemical cues to the transcription apparatus in the nucleus and back to the cell/tissue microenvironment interface through the regulation of cytoskeletal and extracellular matrix components. Their activity is negatively and positively controlled by multiple phosphorylation events. Phenotypically, they serve an important role in cellular plasticity and lineage determination during development. As they regulate self-renewal, proliferation, migration, invasion and differentiation of stem cells, perturbed expression of YAP/TAZ signaling components play important roles in tumorigenesis and metastasis. Despite their high structural similarity, YAP and TAZ are functionally not identical and may play distinct cell type and differentiation stage-specific roles mediated by a diversity of downstream effectors and upstream regulatory molecules. However, YAP and TAZ are frequently looked at as functionally redundant and are not sufficiently discriminated in the scientific literature. As the extracellular matrix composition and mechanosignaling are of particular relevance in bone formation during embryogenesis, post-natal bone elongation and bone regeneration, YAP/TAZ are believed to have critical functions in these processes. Depending on the differentiation stage of mesenchymal stem cells during endochondral bone development, YAP and TAZ serve distinct roles, which are also reflected in bone tumors arising from the mesenchymal lineage at different developmental stages. Efforts to clinically translate the wealth of available knowledge of the pathway for cancer diagnostic and therapeutic purposes focus mainly on YAP and TAZ expression and their role as transcriptional co-activators of TEAD transcription factors but rarely consider the expression and activity of pathway modulatory components and other transcriptional partners of YAP and TAZ. As there is a growing body of evidence for YAP and TAZ as potential therapeutic targets in several cancers, we here interrogate the applicability of this concept to bone tumors. To this end, this review aims to summarize our current knowledge of YAP and TAZ in cell plasticity, normal bone development and bone cancer.Cells 2020, 9, 972 2 of 34 co-activators Yes-associated protein 1 (YAP-1, YAP) and its paralogue, the transcriptional co-activator with PDZ-binding motif (TAZ, WWTR1), which are typically controlled on the post-translational level by upstream regulatory signaling pathways in organ development and tissue homeostasis [2,3]. YAP and TAZ were reported to affect self-renewal and lineage commitment of stem cells [4][5][6][7], while hyperactivation of YAP and TAZ have been linked to cancer growth and metastasis in various tumors [8][9][10]. TAZ levels are elevated in approximately 20% of cancers and drive invasion and metastasis [11,12], while YAP is frequently overexpressed or amplified in cancer and was shown to promote resistance to chemotherapy in oncogene-addicted tumors up...

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Section: Yap and Taz As Regulators Of Osteogenesismentioning

confidence: 99%

Section: Yap and Taz As Regulators Of Osteogenesismentioning

confidence: 99%

The YAP/TAZ Pathway in Osteogenesis and Bone Sarcoma Pathogenesis

Kovar

Bierbaumer

Radic-Sarikas

2020

Cells

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“…In 1999, Panoutsakopoulos et al demonstrated a balanced chromosomal translocation t(16; 17)(q22;p13) as a cytogenetic abnormality in primary aneurysmal bone cyst [7] involving the ubiquitin carboxylterminal hydrolase 6 (USP6) gene, located on chromosome 17p13. Since then, the neoplastic nature of ABC has been established and the USP6 translocation has since been found in approximately 75% of cases [8]. In differentiating primary ABC's from secondary lesions or other tumors such as telangiectatic osteosarcoma this may be an option in selected cases.…”

Section: Introductionmentioning

confidence: 99%

Aneurysmal bone cyst: results of an off label treatment with Denosumab

Dürr¹,

Grahneis²,

Baur‐Melnyk

et al. 2019

BMC Musculoskelet Disord

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Background: The treatment of aneurysmal bone cysts (ABCs) has evolved and less invasive methods have been tried. Denosumab is a monoclonal antibody which inhibits osteoclasts. It has been shown to be effective in giant cell tumour of bone (GCT) of bone and hence promises some effect also in ABC. We report on 6 patients treated with Denosumab and compare our results to the cases already published. Methods: Data of 6 patients with ABCs and patients whose treatment included Denosumab were retrospectively analyzed. Denosumab was used at a dose of 120 mg on days 1, 8, 15 and 29, and every 4 weeks thereafter. In some of these patients the dose was reduced at the end of the treatment. Clinical and radiological responses were evaluated. Results: In 4 female and 2 male patients with a mean age of 17 years (range: 6-30 years) the lesions were located in the sacrum (2), in distal radius, distal femur, talus and pelvis. One of the sacral lesions healed after 12 months and has stayed stable for 3 years since. The second patient received 2 years of therapy with recalcification, but recurred 1 year later and is under renewed therapy. The pelvic lesion improved but recurred. This patient has a 13-years history of intermittent therapy including surgery, two pregnancies and remains in a stable situation. The lesion of the talus did not improve with Denosumab after surgery and was complicated by destruction of the ankle joint with osteoarthritis. Recurrent lesions of the distal femur and the distal radius, previously treated by curettage and bone grafting healed under Denosumab and have remained stable for 2 and 3 years, respectively. One case of severe hypercalcemia was observed in a 7-year old child 6 months after discontinuation of Denosumab. Conclusion: Denosumab provides a treatment option for ABCs in anatomically critical locations. Adjuvant application might reduce the rate of local recurrence. In young patients, severe rebound hypercalcemia months after discontinuation of Denosumab may occur.

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“…bone tumors. Based on these findings, molecular testing as well as specific immunohistochemistry has found its way in routine bone tumor diagnostics that historically heavily relied on morphology and has improved diagnostic accuracy [4,5]. Recently, recurrent translocations in FOS (87%) and FOSB (3%) were found in osteoblastoma and osteoid osteoma [6].…”

Section: Introductionmentioning

confidence: 99%

Utility of FOS as diagnostic marker for osteoid osteoma and osteoblastoma

et al. 2019

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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 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.

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An update of molecular pathology of bone tumors. Lessons learned from investigating samples by next generation sequencing

Cited by 70 publications

References 90 publications

The YAP/TAZ Pathway in Osteogenesis and Bone Sarcoma Pathogenesis

The YAP/TAZ Pathway in Osteogenesis and Bone Sarcoma Pathogenesis

Aneurysmal bone cyst: results of an off label treatment with Denosumab

Utility of FOS as diagnostic marker for osteoid osteoma and osteoblastoma

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