Histological and immunohistochemical features and genetic alterations in the malignant progression of giant cell tumor of bone: a possible association with TP53 mutation and loss of H3K27 trimethylation
Histological and immunohistochemical features and genetic alterations in the malignant progression of giant cell tumor of bone: a possible association with TP53 mutation and loss of H3K27 trimethylation
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DOI：
10.1038/s41379-021-00972-x
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发表时间：
2021-11-16
期刊：
影响因子：
7.5
通讯作者：
Oda, Yoshinao
中科院分区：
文献类型：
--
作者：
Ishihara, Shin;Yamamoto, Hidetaka;Oda, Yoshinao
骨巨细胞瘤（GCTB）在极少数情况下可发生原发性或继发性恶性转化为恶性骨巨细胞瘤（MGCTB），但其分子学改变的细节尚不清楚。本研究旨在阐明MGCTB的临床病理和分子特征的基础上免疫组化，荧光原位杂交（FISH）和下一代测序（NGS）的9个MGCTB（5个原发性和4个继发性）。9例MGCTB中7例（78%）为H3.3 G34 W免疫化学阳性。在2例（22%）患者中，尽管GCTB组分为H3.3 G34 W局灶性或弥漫性阳性，但其恶性组分为H3.3 G34 W完全阴性，这与FISH检测的H3 F3 A杂合丢失相关。4个MGCTB的NGS显示TP 53（n = 3）、EZH 2（n = 1）和其他几个基因的致病性突变。9例MGCTB的免疫组化分析证实了p53核积聚（n = 5）和H3 K27 me 3表达缺失（n = 3），并显示它们是相互排斥的。此外，5例多形性或上皮样细胞为主的MGCTB中有4例（80%）为p53阳性，而4例梭形细胞为主的MGCTB中有3例（75%）为组蛋白3（H3 K27 me 3）赖氨酸27三甲基化阴性。结果提示，以H3 K27 me 3缺失为标志的p53基因改变和组蛋白甲基化功能障碍可能在GCTB的恶性进展中起重要作用，并可能与MGCTB的表型-基因型相关。结合组织学、免疫组化和分子生物学信息可能有助于诊断具有挑战性的病例。
In rare cases, giant cell tumor of bone (GCTB) can undergo primary or secondary malignant transformation to malignant giant cell tumor of bone (MGCTB), but the details of the molecular alterations are still unclear. The present study aimed to elucidate the clinicopathologic and molecular features of MGCTBs based on immunohistochemistry, fluorescence in situ hybridization (FISH) and next generation sequencing (NGS) of nine MGCTBs (five primary and four secondary). Seven (78%) of 9 MGCTBs were immunohistochemically positive for H3.3 G34W. In two (22%) patients, although GCTB components were focally or diffusely positive for H3.3 G34W, their malignant components were entirely negative for H3.3 G34W, which was associated with heterozygous loss of H3F3A by FISH. NGS on four MGCTBs revealed pathogenic mutations in TP53 (n = 3), EZH2 (n = 1) and several other genes. Immunohistochemical analysis of the nine MGCTBs confirmed the p53 nuclear accumulation (n = 5) and loss of H3K27me3 expression (n = 3) and showed that they were mutually exclusive. In addition, four (80%) of five cases of pleomorphic or epithelioid cell-predominant MGCTBs were positive for p53, while three (75%) of four cases of spindle cell-predominant MGCTBs were negative for trimethylation at lysine 27 of histone 3 (H3K27me3). The results suggested that p53 alteration and dysfunction of histone methylation as evidenced by H3K27me3 loss may play an important role in the malignant progression of GCTB, and might contribute to the phenotype-genotype correlation in MGCTB. The combined histologic, immunohistochemical and molecular information may be helpful in part for the diagnosis of challenging cases.