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

T. J. Pugh, W. Yu, J. Yang, A. L. Field, L. Ambrogio, S. L. Carter, K. Cibulskis, P. Giannikopoulos, A. Kiezun, J. Kim, A. McKenna, E. Nickerson, G. Getz, S. Hoffher, Y. H. Messinger, L. P. Dehner, C. W.M. Roberts, C. Rodriguez-Galindo, G. M. Williams, C. T. RossiM. Meyerson, D. A. Hill

Research output: Contribution to journalArticlepeer-review

98 Scopus citations

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.

Original languageEnglish
Pages (from-to)5295-5302
Number of pages8
JournalOncogene
Volume33
Issue number45
DOIs
StatePublished - Nov 6 2014

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