Canada's Michael Smith Genome Sciences Center, BC Cancer Agency, University of British Columbia, Vancouver, British Columbia, Canada.
Leukemia. 2012 Jun;26(6):1383-90. doi: 10.1038/leu.2011.378. Epub 2011 Dec 22.
BCL2 is deregulated in diffuse large B-cell lymphoma (DLBCL) by the t(14;18) translocation, gene amplification and/or nuclear factor-κB signaling. RNA-seq data have recently shown that BCL2 is the most highly mutated gene in germinal center B-cell (GCB) DLBCL. We have sequenced BCL2 in 298 primary DLBCL biopsies, 131 additional non-Hodgkin lymphoma biopsies, 24 DLBCL cell lines and 51 germline DNAs. We found frequent BCL2 mutations in follicular lymphoma (FL) and GCB DLBCL, but low levels of BCL2 mutations in activated B-cell DLBCL, mantle cell lymphoma, small lymphocytic leukemia and peripheral T-cell lymphoma. We found no BCL2 mutations in GC centroblasts. Many mutations were non-synonymous; they were preferentially located in the flexible loop domain, with few in BCL2-homology domains. An elevated transition/transversions ratio supports that the mutations result from somatic hypermutation. BCL2 translocations correlate with, and are likely important in acquisition of, additional BCL2 mutations in GCB DLBCL and FL. DLBCL mutations were not independently associated with survival. Although previous studies of BCL2 mutations in FL have reported mutations to result in pseudo-negative BCL2 protein expression, we find this rare in de-novo DLBCL.
BCL2 在弥漫性大 B 细胞淋巴瘤 (DLBCL) 中被 t(14;18)易位、基因扩增和/或核因子-κB 信号通路失调。最近的 RNA-seq 数据表明，BCL2 是生发中心 B 细胞 (GCB) DLBCL 中突变程度最高的基因。我们对 298 例原发性 DLBCL 活检、131 例非霍奇金淋巴瘤活检、24 例 DLBCL 细胞系和 51 例种系 DNA 进行了 BCL2 测序。我们发现滤泡性淋巴瘤 (FL) 和 GCB DLBCL 中存在频繁的 BCL2 突变，但激活 B 细胞型 DLBCL、套细胞淋巴瘤、小淋巴细胞白血病和外周 T 细胞淋巴瘤中 BCL2 突变水平较低。我们在 GC 中心母细胞中未发现 BCL2 突变。许多突变是非同义突变；它们优先位于柔性环结构域，很少位于 BCL2 同源结构域。较高的转换/颠换比支持这些突变是由体细胞超突变引起的。BCL2 易位与 GCB DLBCL 和 FL 中获得额外的 BCL2 突变相关，并可能很重要。DLBCL 突变与生存无关。尽管以前的 FL 中 BCL2 突变研究报告突变导致 BCL2 蛋白表达呈假阴性，但我们发现这种情况在初发的 DLBCL 中很少见。
