Genome Sciences Centre, BC Cancer Agency, Vancouver, British Columbia, Canada.
Nat Genet. 2010 Feb;42(2):181-5. doi: 10.1038/ng.518. Epub 2010 Jan 17.
Follicular lymphoma (FL) and the GCB subtype of diffuse large B-cell lymphoma (DLBCL) derive from germinal center B cells. Targeted resequencing studies have revealed mutations in various genes encoding proteins in the NF-kappaB pathway that contribute to the activated B-cell (ABC) DLBCL subtype, but thus far few GCB-specific mutations have been identified. Here we report recurrent somatic mutations affecting the polycomb-group oncogene EZH2, which encodes a histone methyltransferase responsible for trimethylating Lys27 of histone H3 (H3K27). After the recent discovery of mutations in KDM6A (UTX), which encodes the histone H3K27me3 demethylase UTX, in several cancer types, EZH2 is the second histone methyltransferase gene found to be mutated in cancer. These mutations, which result in the replacement of a single tyrosine in the SET domain of the EZH2 protein (Tyr641), occur in 21.7% of GCB DLBCLs and 7.2% of FLs and are absent from ABC DLBCLs. Our data are consistent with the notion that EZH2 proteins with mutant Tyr641 have reduced enzymatic activity in vitro.
滤泡性淋巴瘤 (FL) 和生发中心 B 细胞来源的弥漫性大 B 细胞淋巴瘤 (DLBCL) 的 GCB 亚型。靶向重测序研究揭示了 NF-κB 通路中编码蛋白的各种基因的突变，这些突变有助于激活 B 细胞 (ABC) DLBCL 亚型，但迄今为止，仅鉴定出少数 GCB 特异性突变。在这里，我们报告了影响多梳组癌基因 EZH2 的体细胞突变，EZH2 编码一种组蛋白甲基转移酶，负责三甲基化组蛋白 H3 的赖氨酸 27 (H3K27)。在最近发现几种癌症类型中编码组蛋白 H3K27me3 去甲基酶 UTX 的 KDM6A (UTX) 突变后，EZH2 是在癌症中发现的第二个突变的组蛋白甲基转移酶基因。这些突变导致 EZH2 蛋白 SET 结构域中的单个酪氨酸 (Tyr641) 被替换，发生在 21.7%的 GCB DLBCL 和 7.2%的 FL 中，而在 ABC DLBCL 中不存在。我们的数据与 EZH2 蛋白中的突变 Tyr641 具有体外降低的酶活性的观点一致。
