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 model [v1; ref status: approved with reservations 1, http://f1000r.es/5l9]

Authors

Mark Brenneman
Amanda FieldFollow
Jiandong Yang
Gretchen WilliamsFollow
Leslie A. Doros, George Washington University
Christopher T. Rossi, George Washington UniversityFollow
Heather A. Gordish-Dressman, George Washington University
D. Ashley Hill, George Washington UniversityFollow
et al.

Document Type

Journal Article

Publication Date

2015

Journal

F1000 Research

Volume

4

Issue

214

DOI

10.12688/f1000research.6746.1

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.

Comments

Reproduced with permission of F1000 Research.

Creative Commons License

This work is licensed under a Creative Commons Attribution 4.0 License.

APA Citation

Brenneman M, Field A, Yang J, Williams, G, Doros, L et al. (2015). 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 mode [v1; ref status: approved with reservations 1, http://f1000r.es/5l9]. F1000 Research, 4:214.

Peer Reviewed

1

Open Access

1