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Nat Commun. 2019 Aug 15;10(1):3682. doi: 10.1038/s41467-019-11610-1.

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

Author information

1
Department of Developmental Biology, Memorial Sloan-Kettering Cancer Center, New York, NY, 10065, USA.
2
Department of Computational Biology, Memorial Sloan-Kettering Cancer Center, New York, NY, 10065, USA.
3
Tri-Institutional Program in Computational Biology and Medicine, Weill Cornell Medical College, New York, NY, 10065, USA.
4
Marie-Josee and Henry R. Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA.
5
Immunology and Microbiology Department, Medical University of South Carolina, Charleston, SC, 29412, USA.
6
Computational and Systems Biology, Agency for Science Technology and Research, Genome Institute of Singapore, 60 Biopolis Street, Singapore, 138672, Singapore.
7
Oregon Health and Science University, Computational Biology Program, Portland, OR, 97239, USA.
8
Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA.
9
Departments of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA.
10
Department of Computational Biology, Memorial Sloan-Kettering Cancer Center, New York, NY, 10065, USA. sander.research@gmail.com.
11
cBio Center, Dana-Farber Cancer Institute, Boston, MA, 02115, USA. sander.research@gmail.com.
12
Department of Cell Biology, Harvard Medical School, Boston, MA, 02115, USA. sander.research@gmail.com.
13
Department of Developmental Biology, Memorial Sloan-Kettering Cancer Center, New York, NY, 10065, USA. laie@mskcc.org.
14
Tri-Institutional Program in Computational Biology and Medicine, Weill Cornell Medical College, New York, NY, 10065, USA. laie@mskcc.org.

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.

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