DICER1 mutations in familial pleuropulmonary blastoma

Abstract

Pleuropulmonary blastoma (PPB) is a rare pediatric lung tumor that is often part of an inherited cancer syndrome. PPBs consist of mesenchymal cells that are susceptible to malignant transformation and cysts lined by epithelial cells. In a subset of patients, overgrowth of the cysts by mesenchymal cells leads to sarcoma formation. Here, we show that 11 multiplex PPB families harbor heterozygous germline mutations in DICER1, a gene encoding an endoribonuclease critical to the generation of small noncoding regulatory RNAs. Expression of DICER1 protein was undetectable in the epithelial component of PPB tumors but was retained in the malignant mesenchyme (sarcoma). We hypothesize that loss of DICER1 in the epithelium of the developing lung alters the regulation of diffusible factors that promote mesenchymal proliferation.

Figure 1. DICER1 mutations and expression in PPB

(A) DICER1 sequence alteration identified in one of the families in the linkage study. (B) Protein locations of DICER1 mutations in 11 PPB families. Vertical dotted lines with arrows indicate the location of truncating or insertions/deletions in 10 families. Each of these occurs proximal to the RNase III domains. The larger arrow with the solid line marks the location of the missense mutation between the RNase III domains. (C) DICER1 protein is absent in benign-appearing tumor-associated epithelium (arrows) and is present in the mesenchymal tumor cells forming the cambium layer underneath (anti-DICER1 with brown chromagen and hematoxylin counterstain; original magnification x400).