Cancer-associated mutations in DICER1 RNase IIIa and IIIb domains exert similar effects on miRNA biogenesis

Jeffrey Vedanayagam,Nikolaus Schultz,Eric C Lai,Emek Demir,Sonali Majumdar,Walid K Chatila,Bülent Arman Aksoy,Anders Jacobsen Skanderup,Chris Sander

doi:10.1038/s41467-019-11610-1

Abstract

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.

Highlights

Somatic mutations in the RNase IIIb domain of DICER1 arise in cancer and disrupt the cleavage of 5' pre-miRNA arms
We summarize the landscape of somatic DICER1 mutations from 9919 The Cancer Genome Atlas (TCGA) PanCan datasets[28,29], and 31,029 IMPACT datasets acquired from targeted sequencing of MSK patients[30]
Since DICER1 hotspot mutations are overall rare in cancer, we focused on UCEC54, which contained the largest number of DICER1 hotspot mutants (Figs. 1 and 2)

Summary

Introduction

Somatic mutations in the RNase IIIb domain of DICER1 arise in cancer and disrupt the cleavage of 5' pre-miRNA arms. Comprehensive analyses of DICER1 somatic mutations and small RNA data reveal a mechanistic aspect of pre-miRNA processing that manifests in specific cancer settings. Owing to—or perhaps facilitated by—the modest amount of sequence complementarity needed for miRNA regulation, most animal miRNAs appear to have been incorporated into large target networks. There is both computational[5] and experimental[6,7] evidence that individual miRNAs can regulate hundreds of genes. Recent studies reveal that mutation of human DICER1 is cell lethal in human embryonic stem cells[17] This serves as a testament to the detrimental impact of ablating miRNA-mediated regulation. Cancer hotspot mutant variants of DICER1 exhibit selective defects in processing miRNA-5p strands, leading to overall decreases in 5p:3p strand ratios[20,22,23,24,26]

Methods

Results

Conclusion