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H3F3A G34 mutation DNA sequencing and G34W immunohistochemistry analysis in 366 cases of giant cell tumors of bone and other bone tumors.
Histology and Histopathology ( IF 2 ) Pub Date : 2020-10-06 , DOI: 10.14670/hh-18-264
Lihua Gong 1 , Marilyn M Bui 2 , Wen Zhang 1 , Xiaoqi Sun 1 , Ming Zhang 1 , Ding Yi 1
Affiliation  

H3F3A mutations and the expression of glycine 34 to tryptophan (G34W) mutants in giant cell tumors of bone (GCTBs) and other bone tumors were detected to compare H3F3A mutation types and the expression of G34W-mutant protein in order to provide a theoretical basis for using H3F3A mutations as a diagnostic and differential-diagnostic tool for GCTBs. A total of 366 bone tumor cases were investigated. The cases involved 215 men and 151 women, whose median age was 29 years (3-84). The cases included GCTB (n=180), recurrent GCTB (n=19), GCTB with lung metastasis (n=5), pediatric GCTB (n=15), primary malignant GCTB (n=5), chondroblastoma (CB, n=61), chondrosarcoma grade II (n=15), dedifferentiated chondrosarcoma (n=17), chondromyxoid fibroma (n=9), aneurysmal bone cyst (n=9), nonossifying fibroma (n=9), osteosarcoma (n=16), and undifferentiated sarcoma (n=6). Sanger DNA sequencing analysis was used to detect H3F3A mutations. Immunohistochemistry was used to assess the expression of the G34W-mutated protein in these bone tumors. DNA sequencing results revealed H3F3A mutations in 95.00% of GCTBs (171/180), including glycine 34 to tryptophan (G34W, 163/180, 90.56%), glycine 34 to leucine (G34L, 3/180, 1.67%), glycine 34 to valine (G34V, 3/180, 1.67%), and glycine 34 to arginine (G34R, 2/180, 1.11%). Recurrent GCTBs mostly had the H3F3A G34W mutation (18/19, 94.74%), and GCTBs with lung metastasis all had the H3F3A G34W mutation (5/5, 100%). Pediatric GCTBs had a mutation rate of 93.33% (14/15), including one case with G34L. Four cases of primary malignant GCTB showed the H3F3A G34W mutation (4/5, 80.00%), and the classical GCTB component and malignant component showed consistent mutation types. Immunohistochemistry showed that GCTBs harboring G34W also expressed the mutant protein in tumor cell nuclei. Furthermore, one case of GCTB and one case of recurrent GCTB showed positive G34W immunostaining results despite being negative for the genetic mutation. Other bone tumors all showed wild-type expression in both DNA sequencing and immunohistochemistry. Our large-sample DNA sequencing analysis detected four different forms of mutations in GCTBs, including three rare mutation forms. The most common mutation of H3F3A was G34W, which was in accordance with the expression of G34W in GCTBs detected by immunohistochemistry. Although DNA sequencing analysis detected rare mutation types of H3F3A, false-negative results were also present due to the small number of cells in the samples. Detection of the most common (G34W) mutant protein by immunohistochemistry was more convenient. Given the high prevalence of these driver mutations, the detection of H3F3A mutant proteins can assist in the diagnosis of GCTB and its differential diagnosis from other bone tumors.

中文翻译:

366例骨巨细胞瘤及其他骨肿瘤的H3F3A G34突变DNA测序及G34W免疫组化分析[J].

检测骨巨细胞瘤(GCTBs)和其他骨肿瘤中H3F3A突变和甘氨酸34到色氨酸(G34W)突变体的表达,比较H3F3A突变类型和G34W-突变蛋白的表达,以提供理论依据。使用 H3F3A 突变作为 GCTB 的诊断和鉴别诊断工具。共调查了 366 例骨肿瘤病例。病例涉及215名男性和151名女性,中位年龄为29岁(3-84岁)。病例包括GCTB(n=180)、复发性GCTB(n=19)、伴有肺转移的GCTB(n=5)、小儿GCTB(n=15)、原发性恶性GCTB(n=5)、软骨母细胞瘤(CB,n =61)、II 级软骨肉瘤 (n=15)、去分化软骨肉瘤 (n=17)、软骨粘液样纤维瘤 (n=9)、动脉瘤性骨囊肿 (n=9)、非骨化性纤维瘤 (n=9)、骨肉瘤 (n= 16), 和未分化肉瘤(n=6)。Sanger DNA测序分析用于检测H3F3A突变。免疫组织化学用于评估 G34W 突变蛋白在这些骨肿瘤中的表达。DNA 测序结果显示 95.00% (171/180) 的 GCTB 中存在 H3F3A 突变,包括甘氨酸 34 到色氨酸 (G34W, 163/180, 90.56%),甘氨酸 34 到亮氨酸 (G34L, 3/180, 1.6734%)缬氨酸 (G34V, 3/180, 1.67%), 甘氨酸 34 到精氨酸 (G34R, 2/180, 1.11%)。复发性GCTBs多为H3F3A G34W突变(18/19,94.74%),肺转移的GCTBs均存在H3F3A G34W突变(5/5,100%)。儿童 GCTB 的突变率为 93.33% (14/15),其中 1 例为 G34L。4例原发性恶性GCTB显示H3F3A G34W突变(4/5,80.00%),经典GCTB成分和恶性成分显示出一致的突变类型。免疫组织化学表明,携带 G34W 的 GCTBs 也在肿瘤细胞核中表达突变蛋白。此外,1 例 GCTB 和 1 例复发性 GCTB 尽管基因突变为阴性,但 G34W 免疫染色结果呈阳性。其他骨肿瘤在 DNA 测序和免疫组织化学中均显示野生型表达。我们的大样本 DNA 测序分析在 GCTB 中检测到四种不同形式的突变,包括三种罕见的突变形式。H3F3A最常见的突变是G34W,与免疫组化检测GCTBs中G34W的表达一致。尽管 DNA 测序分析检测到 H3F3A 的罕见突变类型,由于样本中的细胞数量很少,也存在假阴性结果。通过免疫组织化学检测最常见的 (G34W) 突变蛋白更方便。鉴于这些驱动突变的高流行率,检测 H3F3A 突变蛋白可以帮助诊断 GCTB 及其与其他骨肿瘤的鉴别诊断。
更新日期:2020-10-08
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