Histone 3.3 hotspot mutations in conventional osteosarcomas: a comprehensive clinical and molecular characterization of six H3F3A mutated cases
Histone 3.3 hotspot mutations in conventional osteosarcomas: a comprehensive clinical and molecular characterization of six H3F3A mutated cases
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DOI：
10.1186/s13569-017-0075-5
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发表时间：
2017-05-04
影响因子：
--
通讯作者：
Mechtersheimer, Gunhild
中科院分区：
文献类型：
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作者：
Koelsche, Christian;Schrimpf, Daniel;Mechtersheimer, Gunhild
背景资料：骨肿瘤中的组蛋白3.3（H3.3）热点突变发生在绝大多数骨巨细胞瘤（GCTB; 96%）、软骨母细胞瘤（95%）和少数骨肉瘤病例中。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是unknown.Methods：在这个多中心，回顾性研究中，共有106个传统的高级别骨肉瘤，在所有年龄组进行了重新检查热点突变的H3.3编码基因H3 F3 A和H3 F3 B。以多学科的方式重新评估H3.3突变型骨肉瘤，并与H3.3野生型骨肉瘤和H3 F3 A G34 W/L突变型GCTBs.Results一起分析全基因组DNA甲基化模式和DNA拷贝数畸变。未发现H3 F3 B突变。所有H3 F3 A突变型骨肉瘤患者年龄均大于30岁，中位年龄为65岁。在高级别骨肉瘤中常见的拷贝数畸变也发生在H3 F3 A突变型骨肉瘤中。与单个H3 F3 A K27 M突变的骨肉瘤不同，H3 F3 A G34 W/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。H3 F3 A G34 W/R突变型与H3.3野生型骨肉瘤中甲基化差异最大的启动子是KLLN/PTEN（p < 0.00005）和HIST 1H 2BB（p < 0.0005）。它们总体上是罕见的，但在30岁以上的骨肉瘤患者中更常见。携带H3 F3 A G34 W/R突变的骨肉瘤与KLLN/PTEN和HIST 1H 2BB的表观遗传失调有关。
Background: 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.Methods: 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 H3F3A and H3F3B. 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 H3F3A G34W/L mutant GCTBs.Results: Six osteosarcomas (6/106) carried H3F3A hotspot mutations. No mutations were found in H3F3B. All patients with H3F3A 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 H3F3A mutant osteosarcomas. Unlike a single osteosarcoma with a H3F3A K27M mutation, the DNA methylation profiles of H3F3A 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 H3F3A G34W/R mutant and H3.3 wild-type osteosarcomas were in KLLN/PTEN (p < 0.00005) and HIST1H2BB (p < 0.0005).Conclusions: H3.3 mutations in osteosarcomas may occur in H3F3A at mutational hotspots. They are overall rare, but become more frequent in osteosarcoma patients older than 30 years. Osteosarcomas carrying H3F3A G34W/R mutations are associated with epigenetic dysregulation of KLLN/PTEN and HIST1H2BB.