Neoplastic transformation is a rare but serious complication of Paget's disease of bone (PDB), occurring in fewer than 1% of individuals with polyostotic disease. Their prognosis is poor, with less than 50% surviving 5 years. In 2016, the genetic alteration of giant cell tumor (GCT) complicating PDB was identified as a founder germline mutation (P937R) in the ZNF687 gene. However, the study population was exclusively of Italian descent, and patients of different ethnic origins were not studied. To fill this gap, herein we performed mutation analysis of ZNF687 in a GCT in the pelvis of a 45‐year‐old black American woman with polyostotic PDB. The P937R mutation in ZNF687 was found in her tumor but, as expected, the ancestral haplotype that characterizes the Italian GCT/PDB patients was not found. Furthermore, we identified two additional Italian GCT/PDB patients with this ZNF687 mutation, now constituting a cohort of 18 GCT/PDB cases, all harboring the identical mutation. We also searched for ZNF687 mutations in a unique collection of tumor tissues derived from Italian PDB patients, including 28 osteosarcomas (OS/PDB), 8 undifferentiated sarcomas (SRC/PDB), 1 fibrosarcoma (FS/PDB), and 1 chondrosarcoma (CS/PDB). We identified the P937R mutation in one SRC/PDB and a different ZNF687 mutation (R331W) in 1 of 28 pagetic osteosarcomas. Thus, whereas GCT/PDB pathogenesis globally seems to involve the P937R mutation in ZNF687, other neoplasms associated with PDB seem to be less related to mutations in this gene. Finally, we identified the G34W mutation in the H3F3A gene in the maxillary tumor masses of two PDB patients, defining them as conventional GCT rather than GCT/PDB. Thus, combined molecular analysis of H3F3A and ZNF687 is essential to clarify the origin and diagnosis of tumors in PDB. © 2020 American Society for Bone and Mineral Research.

中文翻译：

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佩吉特氏骨病的肿瘤变迁扩展队列中的ZNF687突变：对临床病理的影响。

赘生性转化是佩吉特氏骨病（PDB）的罕见但严重的并发症，只有不到1％的多骨变性疾病个体发生。他们的预后很差，存活不到5年的比例不到50％。2016年，与PDB并存的巨细胞瘤（GCT）的遗传变异被确定为ZNF687基因的创始人种系突变（P937R）。但是，研究人群仅是意大利裔，没有研究不同种族血统的患者。为了填补这一空白，我们在一名45岁的美国黑人患有多骨性PDB的女性骨盆中的GCT中对ZNF687进行了突变分析。在P937R突变ZNF687被发现在她的肿瘤中，但不出所料，没有发现代表意大利GCT / PDB患者特征的祖先单体型。此外，我们确定了另外两名具有ZNF687突变的意大利GCT / PDB患者，目前构成了18名GCT / PDB病例队列，所有患者均具有相同的突变。我们还在来自意大利PDB患者的独特肿瘤组织中搜索ZNF687突变，包括28个骨肉瘤（OS / PDB），8个未分化肉瘤（SRC / PDB），1个纤维肉瘤（FS / PDB）和1个软骨肉瘤（CS / PDB）。我们在28个页面性骨肉瘤中的1个中识别出一个SRC / PDB中的P937R突变和一个不同的ZNF687突变（R331W）。因此，尽管全球GCT / PDB发病机制似乎与P937R突变有关ZNF687和其他与PDB相关的肿瘤似乎与该基因的突变关系较小。最后，我们确定了在G34W突变H3F3A基因两个PDB患者的颌骨肿块，将它们定义为传统的GCT而非GCT / PDB。因此，对H3F3A和ZNF687进行联合分子分析对于阐明PDB中的肿瘤起源和诊断至关重要。©2020美国骨骼和矿物质研究学会。