Institute of Genetics and Biophysics "Adriano Buzzati-Traverso", National Research Council of Italy, Naples, Italy.
Center for Metabolic Bone Disease and Molecular Research, Shriners Hospitals for Children-St. Louis, St. Louis, MO, USA; Division of Bone and Mineral Diseases, Department of Internal Medicine, Washington University School of Medicine at Barnes-Jewish Hospital, St. Louis, MO, USA.
Cancer Lett. 2020 Oct 1;489:1-8. doi: 10.1016/j.canlet.2020.05.031. Epub 2020 Jun 2.
Giant cell tumor (GCT) is a bone-destructive benign neoplasm characterized by distinctive multinucleated osteoclast-like giant cells with osteolytic properties distributed among neoplastic stromal cells. GCT is locally aggressive with progressive invasion of adjacent tissues and occasionally displays malignant characteristics including lung metastasis. GCT is characterized genetically by highly recurrent somatic mutations at the G34 position of the H3F3A gene, encoding the histone variant H3.3, in stromal cells. This leads to deregulated gene expression and increased proliferation of mutation-bearing cells. However, when GCT complicates Paget disease of bone (GCT/PDB) it behaves differently, showing a more malignant phenotype with 5-year survival less than 50%. GCT/PDB is caused by a germline mutation in the ZNF687 gene, which encodes a transcription factor involved in the repression of genes surrounding DNA double-strand breaks to promote repair by homologous recombination. Identification of these driver mutations led to novel diagnostic tools for distinguishing between these two tumors and other osteoclast-rich neoplasms. Herein, we review the clinical, histological, and molecular features of GCT in different contexts focusing also on pharmacological treatments.
巨细胞瘤（GCT）是一种破坏性骨良性肿瘤，其特征为具有溶骨性特性的独特多核破骨细胞样巨细胞，分布于肿瘤基质细胞之间。GCT 具有局部侵袭性，可逐渐侵犯邻近组织，偶尔还会表现出恶性特征，包括肺转移。GCT 在遗传学上的特征是，在编码组蛋白变体 H3.3 的 H3F3A 基因的 G34 位置，存在高度反复出现的体细胞突变，这导致突变细胞的基因表达失调和增殖增加。然而，当 GCT 并发骨 Paget 病（GCT/PDB）时，其表现则不同，表现出更具恶性表型的特征，5 年生存率低于 50%。GCT/PDB 是由 ZNF687 基因突变引起的，该基因突变会导致编码一种转录因子的基因失活，该转录因子参与抑制 DNA 双链断裂周围的基因表达，以促进同源重组修复。这些驱动突变的鉴定导致了用于区分这两种肿瘤和其他富含破骨细胞的肿瘤的新诊断工具。本文综述了 GCT 在不同背景下的临床、组织学和分子特征，还重点介绍了药物治疗。
