文章：

滤泡性淋巴瘤中EZH2的改变：生物学和临床相关性

EZH2 alterations in follicular lymphoma: biological and clinical correlations

原文发布日期：2017-04-21

DOI: 10.1038/bcj.2017.32

类型: Original Article

开放获取: 是

英文摘要：

The histone methyltransferase EZH2 has an essential role in the development of follicular lymphoma (FL). Recurrent gain-of-function mutations in EZH2 have been described in 25% of FL patients and induce aberrant methylation of histone H3 lysine 27 (H3K27). We evaluated the role of EZH2 genomic gains in FL biology. Using RNA sequencing, Sanger sequencing and SNP-arrays, the mutation status, copy-number and gene-expression profiles of EZH2 were assessed in a cohort of 159 FL patients from the PRIMA trial. Immunohistochemical (IHC) EZH2 expression (n=55) and H3K27 methylation (n=63) profiles were also evaluated. In total, 37% of patients (59/159) harbored an alteration in the EZH2 gene (mutation n=46, gain n=23). Both types of alterations were associated with highly similar transcriptional changes, with increased proliferation programs. An H3K27me3/me2 IHC score fully distinguished mutated from wild-type samples, showing its applicability as surrogate for EZH2 mutation analysis. However, this score did not predict the presence of gains at the EZH2 locus. The presence of an EZH2 genetic alteration was an independent factor associated with a longer progression-free survival (hazard ratio 0.58, 95% confidence interval 0.36–0.93, P=0.025). We propose that the copy-number status of EZH2 should also be considered when evaluating patient stratification and selecting patients for EZH2 inhibitor-targeted therapies.

摘要翻译： 

组蛋白甲基转移酶EZH2在滤泡性淋巴瘤（FL）的发生发展中起关键作用。25%的FL患者中存在EZH2反复出现的功能获得性突变，该突变会诱导组蛋白H3 lysine 27 (H3K27)的异常甲基化。我们评估了EZH2基因组增益在FL生物学中的作用。通过RNA测序、桑格测序和SNP芯片技术，对PRIMA试验中159例FL患者的EZH2突变状态、拷贝数和基因表达谱进行了评估。同时分析了免疫组化（IHC）的EZH2表达（n=55）和H3K27甲基化（n=63）谱。总计37%的患者（59/159）存在EZH2基因改变（突变n=46，增益n=23）。两种改变类型均与高度相似的转录变化相关，表现为增殖程序上调。H3K27me3/me2免疫组化评分可完全区分突变型与野生型样本，表明其作为EZH2突变分析替代指标的适用性。但该评分不能预测EZH2基因座增益的存在。EZH2遗传改变的存在是与更长无进展生存期相关的独立因素（风险比0.58，95%置信区间0.36–0.93，P=0.025）。我们建议在评估患者分层和选择EZH2抑制剂靶向治疗患者时，应同时考虑EZH2的拷贝数状态。

原文链接：

EZH2 alterations in follicular lymphoma: biological and clinical correlations