Diagnostic value of H3F3A mutations in giant cell tumour of bone compared to osteoclast-rich mimics

Driver mutations in the two histone 3.3 (H3.3) genes, H3F3A and H3F3B, were recently identified by whole genome sequencing in 95% of chondroblastoma (CB) and by targeted gene sequencing in 92% of giant cell tumour of bone (GCT). Given the high prevalence of these driver mutations, it may be possible to utilise these alterations as diagnostic adjuncts in clinical practice. Here, we explored the spectrum of H3.3 mutations in a wide range and large number of bone tumours (n 5 412) to determine if these alterations could be used to distinguish GCT from other osteoclast-rich tumours such as aneurysmal bone cyst, nonossifying fibroma, giant cell granuloma, and osteoclast-rich malignant bone tumours and others. In addition, we explored the driver landscape of GCT through whole genome, exome and targeted sequencing (14 gene panel). We found that H3.3 mutations, namely mutations of glycine 34 in H3F3A, occur in 96% of GCT. We did not find additional driver mutations in GCT, including mutations in IDH1, IDH2, USP6, TP53. The genomes of GCT exhibited few somatic mutations, akin to the picture seen in CB. Overall our observations suggest that the presence of H3F3A p.Gly34 mutations does not entirely exclude malignancy in osteoclast-rich tumours. However, H3F3A p.Gly34 mutations appear to be an almost essential feature of GCT that will aid pathological evaluation of bone tumours, especially when confronted with small needle core biopsies. In the absence of H3F3A p.Gly34 mutations, a diagnosis of GCT should be made with caution.

Complete Public Law Text, Cases and Materials, 3rd edition

Complete Public Law: Text, Cases, and Materials combines extracts from key primary and secondary materials with clear explanatory text to provide a complete resource for students of constitutional and administrative law. Clear, concise explanation of key legal principles is combined with a wide range of extracts, from statutes, case law and academic materials to provide a complete resource for students The authors use straightforward and uncomplicated language to ensure legal concepts and the complexities of the British constitution are easily understood Learning features such as thinking points, diagrams, useful notes, summary points and reflective questions provide valuable support for students and encourage them to engage with the subject A helpful 'case study' chapter on human rights, terrorism and the courts illustrates how the Human Rights Act has been used in practice across the legal system, providing extra insight into the importance of both human rights law and the process of judicial review The 'Judicial review: putting it all together in problem answers' chapter pulls together strands from previous chapters to provide a checklist of issues to be considered in order to diagnose a judicial review problem and advise a client