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Identification of mutations in histones in a number of human neoplasms and developmental syndromes represents the most compelling evidence to date for a causal role of epigenetic perturbations in human disease. In most cases, these mutations have gain of function properties that cause deviation from normal developmental processes leading to embryo defects and/or neoplastic transformation. These exciting discoveries represent a step-change in our understanding of the role of chromatin (dys)regulation in development and disease. However, the mechanisms of action of oncogenic histone mutations (oncohistones) remain only partially understood. Here, we critically assess existing literature on oncohistones focussing mainly on bone neoplasms. We show how it is possible to draw parallels with some of the cell-autonomous mechanisms of action described in paediatric brain cancer, although the functions of oncohistones in bone tumours remain under-investigated. In this respect, it is becoming clear that histone mutations targeting the same residues display, at least in part, tissue-specific oncogenic mechanisms. Furthermore, it is emerging that cancer cells carrying oncohistones can modify the surrounding microenvironment to support growth and/or alter differentiation trajectories. A better understanding of oncohistone function in different neoplasms provide potential for identification of signalling that could be targeted therapeutically. Finally, we discuss some of the main concepts and future directions in this research area, while also drawing possible connections and parallels with other cancer epigenetic mechanisms., Competing Interests: Competing interests: The authors declare no competing interests., (© 2023. The Author(s).)

Osteosarcoma and Ewing sarcoma are bone tumors mostly diagnosed in children, adolescents, and young adults. Despite multimodal therapy, morbidity is high and survival rates remain low, especially in the metastatic disease setting. Trials investigating targeted therapies and immunotherapies have not been groundbreaking. Better understanding of biological subgroups, the role of the tumor immune microenvironment, factors that promote metastasis, and clinical biomarkers of prognosis and drug response are required to make progress. A prerequisite to achieve desired success is a thorough, systematic, and clinically linked biological analysis of patient samples, but disease rarity and tissue processing challenges such as logistics and infrastructure have contributed to a lack of relevant samples for clinical care and research. There is a need for a Europe-wide framework to be implemented for the adequate and minimal sampling, processing, storage, and analysis of patient samples. Two international panels of scientists, clinicians, and patient and parent advocates have formed the Fight Osteosarcoma Through European Research consortium and the Euro Ewing Consortium. The consortia shared their expertise and institutional practices to formulate new guidelines. We report new reference standards for adequate and minimally required sampling (time points, diagnostic samples, and liquid biopsy tubes), handling, and biobanking to enable advanced biological studies in bone sarcoma. We describe standards for analysis and annotation to drive collaboration and data harmonization with practical, legal, and ethical considerations. This position paper provides comprehensive guidelines that should become the new standards of care that will accelerate scientific progress, promote collaboration, and improve outcomes., (©2024 The Authors; Published by the American Association for Cancer Research.)

Paget disease of bone is a metabolic disorder with a strong genetic component, characterised by pronounced disorganised bone remodelling. Complications of this disease include an increased risk of developing bone neoplasms. Here, we describe the case of a 60-year-old Italian patient with Paget disease of bone, presenting with an osteoclast-rich tumour. Our analysis of this entity, based on the clinical, morphological and genetic data (whole exome sequencing), suggests that osteoclast-rich lesions in Paget disease of bone are genetically distinct from classical giant cell tumour of bone. We discuss the importance of differentiating these osteoclast-rich lesions., (© 2023. The Author(s).)

Oncohistones represent compelling evidence for a causative role of epigenetic perturbations in cancer. Giant cell tumours of bone (GCTs) are characterised by a mutated histone H3.3 as the sole genetic driver present in bone-forming osteoprogenitor cells but absent from abnormally large bone-resorbing osteoclasts which represent the hallmark of these neoplasms. While these striking features imply a pathogenic interaction between mesenchymal and myelomonocytic lineages during GCT development, the underlying mechanisms remain unknown. We show that the changes in the transcriptome and epigenome in the mesenchymal cells caused by the H3.3-G34W mutation contribute to increase osteoclast recruitment in part via reduced expression of the TGFβ-like soluble factor, SCUBE3. Transcriptional changes in SCUBE3 are associated with altered histone marks and H3.3 G34W enrichment at its enhancer regions. In turn, osteoclasts secrete unregulated amounts of SEMA4D which enhances proliferation of mutated osteoprogenitors arresting their maturation. These findings provide a mechanism by which GCTs undergo differentiation in response to denosumab, a drug that depletes the tumour of osteoclasts. In contrast, hTERT alterations, commonly found in malignant GCT, result in the histone-mutated neoplastic cells being independent of osteoclasts for their proliferation, predicting unresponsiveness to denosumab. We provide a mechanism for the initiation of GCT, the basis of which is dysfunctional cross-talk between bone-forming and bone-resorbing cells. The findings highlight the role of tumour/microenvironment bidirectional interactions in tumorigenesis and how this is exploited in the treatment of GCT., (© 2022. The Author(s).)