Koelsche Christian, Schrimpf Daniel, Tharun Lars, Roth Eva, Sturm Dominik, Jones David T W, Renker Eva-Kristin, Sill Martin, Baude Annika, Sahm Felix, Capper David, Bewerunge-Hudler Melanie, Hartmann Wolfgang, Kulozik Andreas E, Petersen Iver, Flucke Uta, Schreuder Hendrik W B, Büttner Reinhard, Weber Marc-André, Schirmacher Peter, Plass Christoph, Pfister Stefan M, von Deimling Andreas, Mechtersheimer Gunhild
Department of Neuropathology, Institute of Pathology, University Hospital Heidelberg, Im Neuenheimer Feld 224, 69120 Heidelberg, Germany.
German Cancer Consortium (DKTK), CCU Neuropathology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
Clin Sarcoma Res. 2017 May 4;7:9. doi: 10.1186/s13569-017-0075-5. eCollection 2017.
Histone 3.3 (H3.3) hotspot mutations in bone tumors occur in the vast majority of giant cell tumors of bone (GCTBs; 96%), chondroblastomas (95%) and in a few cases of osteosarcomas. However, clinical presentation, histopathological features, and additional molecular characteristics of H3.3 mutant osteosarcomas are largely unknown.
In this multicentre, retrospective study, a total of 106 conventional high-grade osteosarcomas, across all age groups were re-examined for hotspot mutations in the H3.3 coding genes and . H3.3 mutant osteosarcomas were re-evaluated in a multidisciplinary manner and analyzed for genome-wide DNA-methylation patterns and DNA copy number aberrations alongside H3.3 wild-type osteosarcomas and G34W/L mutant GCTBs.
Six osteosarcomas (6/106) carried hotspot mutations. No mutations were found in . All patients with mutant osteosarcoma were older than 30 years with a median age of 65 years. Copy number aberrations that are commonly encountered in high-grade osteosarcomas also occurred in mutant osteosarcomas. Unlike a single osteosarcoma with a K27M mutation, the DNA methylation profiles of G34W/R mutant osteosarcomas were clearly different from H3.3 wild-type osteosarcomas, but more closely related to GCTBs. The most differentially methylated promoters between G34W/R mutant and H3.3 wild-type osteosarcomas were in (p < 0.00005) and (p < 0.0005).
H3.3 mutations in osteosarcomas may occur in at mutational hotspots. They are overall rare, but become more frequent in osteosarcoma patients older than 30 years. Osteosarcomas carrying G34W/R mutations are associated with epigenetic dysregulation of and .
骨肿瘤中的组蛋白3.3（H3.3）热点突变在绝大多数骨巨细胞瘤（GCTB；96%）、软骨母细胞瘤（95%）以及少数骨肉瘤病例中出现。然而，H3.3突变型骨肉瘤的临床表现、组织病理学特征和其他分子特征在很大程度上尚不清楚。
在这项多中心回顾性研究中，对总共106例所有年龄组的传统高级别骨肉瘤重新检查H3.3编码基因中的热点突变。H3.3突变型骨肉瘤以多学科方式重新评估，并与H3.3野生型骨肉瘤和G34W/L突变型GCTB一起分析全基因组DNA甲基化模式和DNA拷贝数畸变。
6例骨肉瘤（6/106）携带热点突变。未在[此处原文缺失相关基因名称]中发现突变。所有携带[此处原文缺失相关基因名称]突变的骨肉瘤患者年龄均超过30岁，中位年龄为65岁。高级别骨肉瘤中常见的拷贝数畸变也出现在[此处原文缺失相关基因名称]突变型骨肉瘤中。与单个携带K27M突变的骨肉瘤不同，G34W/R突变型骨肉瘤的DNA甲基化谱与H3.3野生型骨肉瘤明显不同，但与GCTB更密切相关。G34W/R突变型和H3.3野生型骨肉瘤之间差异最大的甲基化启动子存在于[此处原文缺失相关基因名称]（p < 0.00005）和[此处原文缺失相关基因名称]（p < 0.0005）中。
骨肉瘤中的H3.3突变可能发生在[此处原文缺失相关基因名称]的突变热点处。它们总体上较为罕见，但在30岁以上的骨肉瘤患者中更为常见。携带G34W/R突变的骨肉瘤与[此处原文缺失相关基因名称]和[此处原文缺失相关基因名称]的表观遗传失调有关。
