Temporal order of RNase IIIb and loss-of-function mutations during development determines phenotype in DICER1 syndrome: a unique variant of the two-hit tumor suppression

Pleuropulmonary blastoma (PPB) is the most frequent pediatric lung tumor and often the first indication of a pleiotropic cancer predisposition, DICER1 syndrome, comprising a range of other individually rare, benign and malignant tumors of childhood and early adulthood. The genetics of -associated DICER1 tumorigenesis are unusual in that tumors typically bear neomorphic missense mutations at one of five specific “hotspot” codons within the RNase IIIb domain of , combined with complete loss of function (LOF) in the other allele. DICER 1 We analyzed a cohort of 124 PPB children for predisposing mutations DICER1 and sought correlations with clinical phenotypes. Over 70% have inherited or germline LOF mutations, most of which truncate the open de novo DICER1 reading frame. We identified a minority of patients who have no germline mutation, but are instead mosaic for predisposing mutations. DICER1 1 1,2 1,2 5,6