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Oncogene DOI:10.1038/onc.2014.150

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.

Publication TypeJournal Article
Year of Publication2014
AuthorsPugh, TJ, Yu, W, Yang, J, Field, AL, Ambrogio, L, Carter, SL, Cibulskis, K, Giannikopoulos, P, Kiezun, A, Kim, J, McKenna, A, Nickerson, E, Getz, G, Hoffher, S, Messinger, YH, Dehner, LP, Roberts, CWM, Rodriguez-Galindo, C, Williams, GM, Rossi, CT, Meyerson, M, Hill, DA
Date Published2014 Nov 06
KeywordsBase Sequence, Chromosomes, Human, Pair 5, DEAD-box RNA Helicases, DNA Copy Number Variations, Exome, Female, Gene Expression Profiling, Gene Expression Regulation, Neoplastic, GTP Phosphohydrolases, Humans, Immunohistochemistry, Lung Neoplasms, Male, Membrane Proteins, MicroRNAs, Mutation, Nucleic Acid Conformation, Oligonucleotide Array Sequence Analysis, Proto-Oncogene Proteins B-raf, Pulmonary Blastoma, Reverse Transcriptase Polymerase Chain Reaction, Ribonuclease III, Sequence Analysis, DNA, Tumor Suppressor Protein p53

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.


Alternate JournalOncogene
PubMed ID24909177
PubMed Central IDPMC4224628
Grant ListR01HL109265 / HL / NHLBI NIH HHS / United States
R01 CA143167 / CA / NCI NIH HHS / United States
R01HL111190 / HL / NHLBI NIH HHS / United States
R01 HL111190 / HL / NHLBI NIH HHS / United States
R01 HL109265 / HL / NHLBI NIH HHS / United States