Department of Developmental Biology, Memorial Sloan-Kettering Cancer Center, New York, NY, 10065, USA.
Department of Computational Biology, Memorial Sloan-Kettering Cancer Center, New York, NY, 10065, USA.
Nat Commun. 2019 Aug 15;10(1):3682. doi: 10.1038/s41467-019-11610-1.
Somatic mutations in the RNase IIIb domain of DICER1 arise in cancer and disrupt the cleavage of 5' pre-miRNA arms. Here, we characterize an unstudied, recurrent, mutation (S1344L) in the DICER1 RNase IIIa domain in tumors from The Cancer Genome Atlas (TCGA) project and MSK-IMPACT profiling. RNase IIIa/b hotspots are absent from most cancers, but are notably enriched in uterine cancers. Systematic analysis of TCGA small RNA datasets show that DICER1 RNase IIIa-S1344L tumors deplete 5p-miRNAs, analogous to RNase IIIb hotspot samples. Structural and evolutionary coupling analyses reveal constrained proximity of RNase IIIa-S1344 to the RNase IIIb catalytic site, rationalizing why mutation of this site phenocopies known hotspot alterations. Finally, examination of DICER1 hotspot endometrial tumors reveals derepression of specific miRNA target signatures. In summary, comprehensive analyses of DICER1 somatic mutations and small RNA data reveal a mechanistic aspect of pre-miRNA processing that manifests in specific cancer settings.
DICER1 的 RNase IIIb 结构域中的体细胞突变出现在癌症中，并破坏了 5' 前体 miRNA 臂的切割。在这里，我们描述了一种在癌症基因组图谱 (TCGA) 项目和 MSK-IMPACT 分析中尚未研究的、复发性的 DICER1 RNase IIIa 结构域突变（S1344L）。大多数癌症中不存在 RNase IIIa/b 热点，但在子宫癌中明显富集。对 TCGA 小 RNA 数据集的系统分析表明，DICER1 RNase IIIa-S1344L 肿瘤耗尽了 5p-miRNAs，类似于 RNase IIIb 热点样本。结构和进化耦合分析表明，RNase IIIa-S1344 与 RNase IIIb 催化位点的紧密接近受到限制，这解释了为什么该位点的突变与已知的热点改变相似。最后，对 DICER1 热点子宫内膜肿瘤的检查揭示了特定 miRNA 靶标特征的去抑制。总之，对 DICER1 体细胞突变和小 RNA 数据的综合分析揭示了 miRNA 前体加工的一个机制方面，在特定的癌症环境中表现出来。
