Somatic mutations in DROSHA and DICER1 impair microRNA biogenesis through distinct mechanisms in Wilms tumours.
Somatic mutations in DROSHA and DICER1 impair microRNA biogenesis through distinct mechanisms in Wilms tumours.
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DOI：
10.1038/ncomms5802
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发表时间：
2014-09-05
影响因子：
16.6
通讯作者：
Amatruda, James F.
中科院分区：
文献类型：
--
作者：
Rakheja, Dinesh;Chen, Kenneth S.;Liu, Yangjian;Shukla, Abhay A.;Schmid, Vanessa;Chang, Tsung-Cheng;Khokhar, Shama;Wickiser, Jonathan E.;Karandikar, Nitin J.;Malter, James S.;Mendell, Joshua T.;Amatruda, James F.
肾母细胞瘤是最常见的儿童肾癌。在这里，我们报告了44个肾母细胞瘤的全外显子组测序，确定了microRNA（miRNA）加工酶DROSHA和DICER 1的错义突变，以及MYCN，SMARCA 4和ARID 1A的新突变。对肿瘤miRNA表达、体外加工测定和人类细胞中的基因组编辑的检查表明，DICER 1和DROSHA突变通过不同的机制影响miRNA加工。DICER 1 RNase IIIB突变优先损害来自前体miRNA发夹5′臂的miRNA的加工，而DROSHA RNase IIIB突变通过显性负性机制全面抑制miRNA生物合成。DROSHA和DICER 1突变都损害了肿瘤抑制miRNA的表达，包括let-7家族，MYCN，LIN 28和其他Wilms肿瘤癌基因的重要调节因子。这些结果提供了新的见解的机制，通过突变的miRNA生物合成组件重新编程的miRNA表达在人类癌症，并表明这些缺陷定义了一个独特的亚类肾母细胞瘤。 肾母细胞瘤是一种常见的儿童癌症。在这里，作者在44个Wilms肿瘤中使用全外显子组测序来表征它们的突变景观，并表明DICER 1和DROSHA突变可以抑制肿瘤抑制microRNA的生物发生。
Wilms tumour is the most common childhood kidney cancer. Here we report the whole-exome sequencing of 44 Wilms tumours, identifying missense mutations in the microRNA (miRNA)-processing enzymes DROSHA and DICER1, and novel mutations in MYCN, SMARCA4 and ARID1A. Examination of tumour miRNA expression, in vitro processing assays and genomic editing in human cells demonstrates that DICER1 and DROSHA mutations influence miRNA processing through distinct mechanisms. DICER1 RNase IIIB mutations preferentially impair processing of miRNAs deriving from the 5′-arm of pre-miRNA hairpins, while DROSHA RNase IIIB mutations globally inhibit miRNA biogenesis through a dominant-negative mechanism. Both DROSHA and DICER1 mutations impair expression of tumour-suppressing miRNAs, including the let-7 family, important regulators of MYCN, LIN28 and other Wilms tumour oncogenes. These results provide new insights into the mechanisms through which mutations in miRNA biogenesis components reprogramme miRNA expression in human cancer and suggest that these defects define a distinct subclass of Wilms tumours. Wilms tumour is a common childhood cancer. Here, the authors use whole-exome sequencing in 44 Wilms tumours to characterize their mutational landscape and show that DICER1 and DROSHA mutations can suppress the biogenesis of tumour-suppressing microRNAs.
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影响因子：
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作者：
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