Kervarrec Thibault, Collin Christine, Larousserie Frédérique, Bouvier Corinne, Aubert Sébastien, Gomez-Brouchet Anne, Marie Béatrice, Miquelestorena-Standley Elodie, Le Nail Louis Romée, Avril Pierre, Christophe Pagès Jean, de Pinieux Gonzague
Department of Pathology, University Hospital of Tours, Avenue de la République, Chambray-les-tours, France.
Molecular Biology Platforms, University Hospital of Tours, Avenue de la République, Chambray-les-tours, France.
Mod Pathol. 2017 Mar;30(3):393-406. doi: 10.1038/modpathol.2016.212. Epub 2017 Jan 6.
Behjati et al recently described recurrent mutations of H3F3 genes in giant cell tumors of the bone and chondroblastomas. Both these entities belong to the spectrum of giant cell-rich bone lesions, often presenting a diagnostic challenge for the pathologist. Our aim was to investigate the value of searching for H3F3 mutations in the diagnosis of giant cell tumors of the bone and giant cell-rich chondroblastomas. Two hundred eighty-one bone lesion samples, including 170 giant cell tumors of the bone, 26 chondroblastomas and 85 other giant cell-rich and/or epiphyseal tumors, were analyzed. Mutation status was determined using first high resolution melting screening and then mutation profiling pyrosequencing. Mutational status was compared with clinical data and, for giant cell tumors of the bone, with p63 immunostaining status. As histone methylation changes have been reported in association with H3F3 mutations, the methylation status of lysine 37 was investigated. H3F3A and H3F3B were found in 85% of giant cell tumors of the bone and 88% of chondroblastomas. In addition to the major G35W mutation, we found two rare H3F3A mutations: one G35R and one G35V. Among the other tumors studied, we only found H3F3A gene mutations in two cases of 'dedifferentiated chondrosarcoma mimicking giant cell tumor of the bone'. A H3F3B mutation was also observed in one case of dedifferentiated chondroblastoma. P63 expression in giant cell tumors of the bone seems to be associated with H3F3 gene mutations (P=0.004). H3F3 mutations did not correlate with clinical data, outcome or methylation changes in Lysin 37. In conclusion, H3F3 mutations are sensitive and specific markers of giant cell tumors of the bone and chondroblastomas. High resolution melting and pyrosequencing procedures are high-performance tools in this context. Determination of H3F3 mutation will allow reclassification of some entities belonging to the spectrum of giant cell-rich lesions.
贝贾蒂等人最近描述了骨巨细胞瘤和成软骨细胞瘤中H3F3基因的复发性突变。这两种病变都属于富含巨细胞的骨病变范畴，常常给病理学家带来诊断挑战。我们的目的是研究在骨巨细胞瘤和富含巨细胞的成软骨细胞瘤诊断中寻找H3F3突变的价值。分析了281份骨病变样本，包括170例骨巨细胞瘤、26例成软骨细胞瘤以及85例其他富含巨细胞和/或骨骺肿瘤。首先使用高分辨率熔解筛选，然后通过焦磷酸测序进行突变分析来确定突变状态。将突变状态与临床数据进行比较，对于骨巨细胞瘤，还与p63免疫染色状态进行比较。由于已有报道组蛋白甲基化变化与H3F3突变相关，因此研究了赖氨酸37的甲基化状态。在85%的骨巨细胞瘤和88%的成软骨细胞瘤中发现了H3F3A和H3F3B。除了主要的G35W突变外，我们还发现了两个罕见的H3F3A突变：一个G35R和一个G35V。在其他研究的肿瘤中，仅在两例“模仿骨巨细胞瘤的去分化软骨肉瘤”中发现了H3F3A基因突变。在一例去分化成软骨细胞瘤中也观察到了H3F3B突变。骨巨细胞瘤中的p63表达似乎与H3F3基因突变相关（P = 0.004）。H3F3突变与临床数据、预后或赖氨酸37的甲基化变化无关。总之，H3F3突变是骨巨细胞瘤和成软骨细胞瘤敏感且特异的标志物。在这种情况下，高分辨率熔解和焦磷酸测序程序是高效工具。H3F3突变的测定将有助于对一些属于富含巨细胞病变范畴的实体进行重新分类。
