文章：

CCND1体细胞异常高突变产生套细胞淋巴瘤发生的非编码驱动因子

Aberrant somatic hypermutation of CCND1 generates non-coding drivers of mantle cell lymphomagenesis 

原文发布日期：2022-02-10 

英文摘要：

Aberrant somatic hypermutation (aSHM) can target proto-oncogenes and drive oncogenesis. In mantle cell lymphoma (MCL), CCND1 is targeted by aSHM in the non-nodal subtype (nnMCL), giving rise to exon1 encoded mutant proteins like E36K, Y44D, and C47S that contribute to lymphomagenesis by virtue of their increased protein stability and nuclear localization. However, the vast majority of somatic variants generated by aSHM are found in the first intron of CCND1 but their significance for mantle cell lymphomagenesis is unknown. We performed whole-genome and whole-transcriptome sequencing in 84 MCL patients to explore the contribution of non-coding somatic variants created by aSHM to lymphomagenesis. We show that non-coding variants are enriched in a MCL specific manner in transcription factor-binding sites, that non-coding variants are associated with increased CCND1 mRNA expression, and that coding variants in the first exon of CCND1 are more often synonymous or cause benign amino acid changes than in other types of lymphomas carrying a t(11;14) translocation. Therefore, the increased frequency of somatic variants due to aSHM might be a consequence of selection pressure manifested at the transcriptional level rather than being a mere mechanistic consequence of misguided activation-induced cytidine deaminase (AID) activity. 

摘要翻译： 

异常体细胞超突变（aSHM）可靶向原癌基因并驱动肿瘤发生。在套细胞淋巴瘤（MCL）中，CCND1基因在非结性亚型（nnMCL）中受到aSHM的靶向攻击，产生如E36K、Y44D和C47S等由第一外显子编码的突变蛋白——这些蛋白通过增强的稳定性和核定位能力促进淋巴瘤生成。然而，绝大多数由aSHM产生的体细胞变异集中于CCND1的第一内含子区域，这些变异对套细胞淋巴瘤发生的意义尚不明确。通过对84例MCL患者进行全基因组和全转录组测序，我们探索了aSHM产生的非编码体细胞变异对淋巴瘤发生的贡献。研究发现：非编码变异以MCL特异性的方式富集于转录因子结合位点；非编码变异与CCND1 mRNA表达升高相关；与携带t(11;14)易位的其他淋巴瘤类型相比，CCND1第一外显子中的编码变异更常为同义突变或导致良性氨基酸改变。因此，aSHM所致体细胞变异频率的升高可能是转录水平选择压力的结果，而不仅仅是错误激活的胞苷脱氨酶（AID）活性机制性作用的产物。

原文链接：

Aberrant somatic hypermutation of CCND1 generates non-coding drivers of mantle cell lymphomagenesis