RESUMO
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.
Assuntos
RNA Helicases DEAD-box/genética , Neoplasias Pulmonares/genética , MicroRNAs/genética , Mutação , Blastoma Pulmonar/genética , Ribonuclease III/genética , Proteína Supressora de Tumor p53/genética , Sequência de Bases , Cromossomos Humanos Par 5/genética , RNA Helicases DEAD-box/metabolismo , Variações do Número de Cópias de DNA , Exoma/genética , Feminino , GTP Fosfo-Hidrolases/genética , GTP Fosfo-Hidrolases/metabolismo , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Humanos , Imuno-Histoquímica , Neoplasias Pulmonares/metabolismo , Masculino , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , MicroRNAs/química , Conformação de Ácido Nucleico , Análise de Sequência com Séries de Oligonucleotídeos , Proteínas Proto-Oncogênicas B-raf/genética , Proteínas Proto-Oncogênicas B-raf/metabolismo , Blastoma Pulmonar/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Ribonuclease III/metabolismo , Análise de Sequência de DNA/métodos , Proteína Supressora de Tumor p53/metabolismoRESUMO
The SWI/SNF chromatin remodeling complex is a master regulator of developmental cell-fate decisions, although the key target pathways are poorly characterized. Here, we interrogated the contribution of the SWI/SNF subunit and tumor suppressor SNF5 to the regulation of developmental pathways using conditional mouse and cell culture models. We find that loss of SNF5 phenocopies ß-catenin hyperactivation and that SNF5 is essential for regulating Wnt/ß-catenin pathway target expression. These data provide insight into chromatin-based mechanisms that underlie developmental regulation and elucidate the emerging theme that mutation of this tumor suppressor complex can activate developmental pathways by uncoupling them from upstream control.