The DICER1 syndrome, also known as the pleuropulmonary blastoma familial tumor dysplasia syndrome (PPB-FTDS) (OMIM #601200), is a recently described entity comprising a number of rare to ultra-rare tumors arising mainly in childhood or adolescence. The most frequent and characteristic disorders are pleuropulmonary blastoma, cystic nephroma and ovarian Sertoli-Leydig cell tumors. Some aspects of the syndrome were identified in the 1970s and 1990s, but discovery in 2009 by Hill et al of heterozygous disease-associated germ-line DICER1 mutations in affected kindred brought the syndrome into focus. Several studies since 2009 have extended the phenotypes to include more common conditions such as multinodular goiter and Wilms tumor, as well as much rarer entities such as cervical embryonal rhabdomyosarcoma, pineoblastoma and pituitary blastoma. The critical molecular defect appears to be impairment of DICER1's RNase III endonuclease function, which normally would cleave precursor microRNAs to their final mature length. These microRNAs function by targeted silencing and/or degradation of specific messenger RNAs. DICER1 may be considered an unusual type of tumor suppressor gene, in that the first inherited “hit” usually cripples one allele completely, whereas a second somatic “hit” is nearly always limited to the RNase III domains (and is in fact often even more focused on the metal-binding domains of RNase IIIb). These second hits are most commonly a single base substitution leading to an amino acid change, which functionally impairs the protein without overall protein loss. In this presentation I will summarize the current knowledge on the role of DICER1 mutations in cancer and will describe the edges of the known associated phenotypes.

Citation Format: William D. Foulkes, Mona Wu, Leanne De Kock, Leora Witkowski, Nelly Sabbaghian, Evan Weber, Nancy Hamel, John R. Priest. DICER1: From ontogenesis to oncogenesis. [abstract]. In: Proceedings of the AACR Special Conference: Cancer Susceptibility and Cancer Susceptibility Syndromes; Jan 29-Feb 1, 2014; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(23 Suppl):Abstract nr IA03. doi:10.1158/1538-7445.CANSUSC14-IA03

©2014 American Association for Cancer Research.
2014