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Oncogene. 2014 Nov 6;33(45):5295-302. doi: 10.1038/onc.2014.150. Epub 2014 Jun 9.

Exome sequencing of pleuropulmonary blastoma reveals frequent biallelic loss of TP53 and two hits in DICER1 resulting in retention of 5p-derived miRNA hairpin loop sequences.

Author information

1
1] Broad Institute of MIT and Harvard, Cambridge, MA, USA [2] Dana-Farber Cancer Institute, Boston, MA, USA [3] Harvard Medical School, Boston, MA, USA.
2
1] Department of Integrative Systems Biology, George Washington University, Washington, DC, USA [2] Center for Genetic Medicine Research and Department of Pathology, Children's National Medical Center, Washington, DC, USA.
3
Broad Institute of MIT and Harvard, Cambridge, MA, USA.
4
Children's Hospitals and Clinics of Minnesota, Minneapolis, MN, USA.
5
Department of Pathology and Immunology, Washington University Medical Center, St Louis, MO, USA.
6
1] Dana-Farber Cancer Institute, Boston, MA, USA [2] Harvard Medical School, Boston, MA, USA [3] Boston Children's Hospital, Boston, MA, USA [4] Dana-Farber/Children's Cancer Center, Boston, MA, USA.
7
Department of Integrative Systems Biology, George Washington University, Washington, DC, USA.

Abstract

Pleuropulmonary blastoma is a rare childhood malignancy of lung mesenchymal cells that can remain dormant as epithelial cysts or progress to high-grade sarcoma. Predisposing germline loss-of-function DICER1 variants have been described. We sought to uncover additional contributors through whole exome sequencing of 15 tumor/normal pairs, followed by targeted resequencing, miRNA analysis and immunohistochemical analysis of additional tumors. In addition to frequent biallelic loss  of TP53 and mutations of NRAS or BRAF in some cases, each case had compound disruption of DICER1: a germline (12 cases) or somatic (3 cases) loss-of-function variant plus a somatic missense mutation in the RNase IIIb domain. 5p-Derived microRNA (miRNA) transcripts retained abnormal precursor miRNA loop sequences normally removed by DICER1. This work both defines a genetic interaction landscape with DICER1 mutation and provides evidence for alteration in miRNA transcripts as a consequence of DICER1 disruption in cancer.

PMID:
24909177
PMCID:
PMC4224628
DOI:
10.1038/onc.2014.150
[Indexed for MEDLINE]
Free PMC Article
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