title: 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.
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.
authors.affiliation: 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.
authors.forename: T J
authors.initials: TJ
authors.lastname: Pugh
authors.affiliation: 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.
authors.forename: W
authors.initials: W
authors.lastname: Yu
authors.affiliation: 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.
authors.forename: J
authors.initials: J
authors.lastname: Yang
authors.affiliation: 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.
authors.forename: A L
authors.initials: AL
authors.lastname: Field
authors.affiliation: Broad Institute of MIT and Harvard, Cambridge, MA, USA.
authors.forename: L
authors.initials: L
authors.lastname: Ambrogio
authors.affiliation: Broad Institute of MIT and Harvard, Cambridge, MA, USA.
authors.forename: S L
authors.initials: SL
authors.lastname: Carter
authors.affiliation: Broad Institute of MIT and Harvard, Cambridge, MA, USA.
authors.forename: K
authors.initials: K
authors.lastname: Cibulskis
authors.affiliation: Broad Institute of MIT and Harvard, Cambridge, MA, USA.
authors.forename: P
authors.initials: P
authors.lastname: Giannikopoulos
authors.affiliation: Broad Institute of MIT and Harvard, Cambridge, MA, USA.
authors.forename: A
authors.identifier: 0000000266341073
authors.initials: A
authors.lastname: Kiezun
authors.affiliation: Broad Institute of MIT and Harvard, Cambridge, MA, USA.
authors.forename: J
authors.initials: J
authors.lastname: Kim
authors.affiliation: Broad Institute of MIT and Harvard, Cambridge, MA, USA.
authors.forename: A
authors.initials: A
authors.lastname: McKenna
authors.affiliation: Broad Institute of MIT and Harvard, Cambridge, MA, USA.
authors.forename: E
authors.initials: E
authors.lastname: Nickerson
authors.affiliation: Broad Institute of MIT and Harvard, Cambridge, MA, USA.
authors.forename: G
authors.initials: G
authors.lastname: Getz
authors.affiliation: 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.
authors.forename: S
authors.initials: S
authors.lastname: Hoffher
authors.affiliation: Children's Hospitals and Clinics of Minnesota, Minneapolis, MN, USA.
authors.forename: Y H
authors.initials: YH
authors.lastname: Messinger
authors.affiliation: Department of Pathology and Immunology, Washington University Medical Center, St Louis, MO, USA.
authors.forename: L P
authors.initials: LP
authors.lastname: Dehner
authors.affiliation: 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.
authors.forename: C W M
authors.initials: CW
authors.lastname: Roberts
authors.affiliation: 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.
authors.forename: C
authors.initials: C
authors.lastname: Rodriguez-Galindo
authors.affiliation: Children's Hospitals and Clinics of Minnesota, Minneapolis, MN, USA.
authors.forename: G M
authors.initials: GM
authors.lastname: Williams
authors.affiliation: Department of Integrative Systems Biology, George Washington University, Washington, DC, USA.
authors.forename: C T
authors.initials: CT
authors.lastname: Rossi
authors.affiliation: 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.
authors.forename: M
authors.initials: M
authors.lastname: Meyerson
authors.affiliation: 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.
authors.forename: D A
authors.initials: DA
authors.lastname: Hill
mesh_terms: D001483:Base Sequence; D002895:Chromosomes, Human, Pair 5 / Q000235:genetics; D053487:DEAD-box RNA Helicases / Q000235:genetics* / Q000378:metabolism; D056915:DNA Copy Number Variations; D059472:Exome / Q000235:genetics; D005260:Female; D020558:GTP Phosphohydrolases / Q000235:genetics / Q000378:metabolism; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007150:Immunohistochemistry; D008175:Lung Neoplasms / Q000235:genetics* / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D035683:MicroRNAs / Q000737:chemistry / Q000235:genetics*; D009154:Mutation; D009690:Nucleic Acid Conformation; D020411:Oligonucleotide Array Sequence Analysis; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics / Q000378:metabolism; D018202:Pulmonary Blastoma / Q000235:genetics* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D043244:Ribonuclease III / Q000235:genetics* / Q000378:metabolism; D017422:Sequence Analysis, DNA / Q000379:methods; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000378:metabolism
chemical_list: D008565:Membrane Proteins; D035683:MicroRNAs; D016159:Tumor Suppressor Protein p53; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; C408087:DICER1 protein, human; D043244:Ribonuclease III; D020558:GTP Phosphohydrolases; C579846:NRAS protein, human; D053487:DEAD-box RNA Helicases