Year: 2025
Type: dataset
Abstract: 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 DICER1 -associated tumorigenesis are unusual in that tumors typically bear neomorphic missense mutations at one of five specific “hotspot” codons within the RNase IIIb domain of DICER 1 , combined with complete loss of function (LOF) in the other allele. We analyzed a cohort of 124 PPB children for predisposing DICER1 mutations and sought correlations with clinical phenotypes. Over 70% have inherited or de novo germline LOF mutations, most of which truncate the DICER1 open reading frame. We identified a minority of patients who have no germline mutation, but are instead mosaic for predisposing DICER1 mutations. Mosaicism for RNase IIIb domain hotspot mutations defines a special category of DICER1 syndrome patients, clinically distinguished from those with germline or mosaic LOF mutations by earlier onsets and numerous discrete foci of neoplastic disease involving multiple syndromic organ sites. A final category of patients lack predisposing germline or mosaic mutations and have disease limited to a single PPB tumor bearing tumor-specific RNase IIIb and LOF mutations. We propose that acquisition of a neomorphic RNase IIIb domain mutation is the rate limiting event in DICER1 -associated tumorigenesis, and that distinct clinical phenotypes associated with mutational categories reflect the temporal order in which LOF and RNase IIIb domain mutations are acquired during development.
Authors: Mark Brenneman, Amanda Field, Jiandong Yang, Gretchen Williams, Leslie Doros, Christopher Rossi, Kris Ann Schultz, Avi Rosenberg, Jennifer Ivanovich, Joyce Turner, Heather Gordish-Dressman, Douglas Stewart, Weiying Yu, Anne Harris, Peter Schoettler, Paul Goodfellow, Louis Dehner, Yoav Messinger, D. Ashley Hill
Institutions: Children's National, George Washington University, Children's Minnesota, Johns Hopkins University, Johns Hopkins Medicine, Washington University in St. Louis, Washington University Medical Center, National Institutes of Health, National Cancer Institute, Division of Cancer Epidemiology and Genetics, The Ohio State University
Language: English
Subfield: Surgery
Field: Medicine
Domain: Health Sciences
Open Access status: gold
OpenAlex ID: W4416598556