Comparative Transcriptome Analyses Highlight Distinct Pathogenetic Mechanisms for Pleuropulmonary Blastoma and Congenital Pulmonary Airway Malformations

ABSTRACT: Pleuropulmonary blastoma (PPB) and congenital pulmonary airway malformations (CPAM) are two rare cystic lung diseases occurring in childhood. PPB can evolve from a low-grade epithelial cyst lesion to a high-grade sarcoma with a poor prognosis, whereas CPAM usually has a favorable non-tumorous outcome. Clinical similarities complicate diagnosis and may delay appropriate care. PPB is associated with DICER1 mutations that disturb miRNA biogenesis, altering the miRNA repertoire. Conversely, KRAS mutations are detected in CPAM, but their implication remains unclear. To decipher the mechanisms underlying these diseases, we undertook a comprehensive analysis of molecular variations in CPAM and PPB lung lesions using genome-wide RNA-seq and miRNA-seq assays. Each pathology displayed a distinct expression profile revealing a unique etiology. CPAM presented misexpression of bronchial epithelial markers correlating with KRAS mutation, while changes in expression of distal lung epithelial and mesenchymal markers were PPB-specific. PPB also exhibited abnormal gain of expression of developmental transcription factors, likely due to perturbed Polycomb Repressive Complex 2 (PRC2) activity. Overexpression of miR-323a-3p, which targets the PRC2 subunit EED, correlated with decreased EED expression. Together, these observations propose a PPB pathogenetic mechanism connecting DICER1 mutations and altered miRNA profile to defective PRC2 activity, misexpression of developmental transcription factors, and cancer.