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 Rossi; M Meyerson; D A Hill

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

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

Authors

T J Pugh¹, W Yu², J Yang², A L Field², L Ambrogio³, S L Carter³, K Cibulskis³, P Giannikopoulos³, A Kiezun³, J Kim³, A McKenna³, E Nickerson³, G Getz³, S Hoffher², Y H Messinger⁴, L P Dehner⁵, C W M Roberts⁶, C Rodriguez-Galindo⁶, G M Williams⁴, C T Rossi⁷, M Meyerson¹, D A Hill²

Affiliations

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.

Publication types

Research Support, N.I.H., Extramural

MeSH terms

Base Sequence
Chromosomes, Human, Pair 5 / genetics
DEAD-box RNA Helicases / genetics*
DEAD-box RNA Helicases / metabolism
DNA Copy Number Variations
Exome / genetics
Female
GTP Phosphohydrolases / genetics
GTP Phosphohydrolases / metabolism
Gene Expression Profiling
Gene Expression Regulation, Neoplastic
Humans
Immunohistochemistry
Lung Neoplasms / genetics*
Lung Neoplasms / metabolism
Male
Membrane Proteins / genetics
Membrane Proteins / metabolism
MicroRNAs / chemistry
MicroRNAs / genetics*
Mutation*
Nucleic Acid Conformation
Oligonucleotide Array Sequence Analysis
Proto-Oncogene Proteins B-raf / genetics
Proto-Oncogene Proteins B-raf / metabolism
Pulmonary Blastoma / genetics*
Pulmonary Blastoma / metabolism
Reverse Transcriptase Polymerase Chain Reaction
Ribonuclease III / genetics*
Ribonuclease III / metabolism
Sequence Analysis, DNA / methods
Tumor Suppressor Protein p53 / genetics*
Tumor Suppressor Protein p53 / metabolism

Substances

Membrane Proteins
MicroRNAs
Tumor Suppressor Protein p53
BRAF protein, human
Proto-Oncogene Proteins B-raf
DICER1 protein, human
Ribonuclease III
GTP Phosphohydrolases
NRAS protein, human
DEAD-box RNA Helicases

Supplementary concepts

Pleuropulmonary blastoma

Abstract

Publication types

MeSH terms

Substances

Supplementary concepts

Grants and funding