Major finding: Somatic DICER1 hot-spot mutations occur in 29% of nonepithelial ovarian cancers.
Mechanism: DICER1 RNase IIIb domain mutations impair miRNA but not miRNA* strand cleavage.
Impact: Residual DICER1 function may be oncogenic in specific cellular contexts.
Sex cord–stromal tumors and germ cell tumors are rare nonepithelial variants of ovarian cancer for which the pathogenesis is poorly understood. Heravi-Moussavi and colleagues performed whole-exome and whole-transcriptome sequencing of 14 nonepithelial ovarian tumors and identified 4 heterozygous nonsynonymous missense mutations in the microRNA (miRNA) processing gene DICER1. Because these mutations were closely clustered in a hot spot encompassing the metal-binding residues of the DICER1 RNase IIIb domain, the authors sequenced this region in a validation set of 102 additional nonepithelial ovarian cancers. DICER1 hot-spot mutations were identified in 30 of these tumors, with the vast majority occurring in Sertoli-Leydig cell tumors, a subtype of ovarian sex cord–stromal tumors. In total, 60% of the Sertoli-Leydig cell tumors included in the validation set harbored a DICER1 mutation. The authors performed in vitro RNA cleavage assays to determine the effect of these hot-spot mutations on DICER1 activity and showed that these mutants had severely impaired RNase IIIb activity that affected cleavage of the miRNA targeting strand. However, the mutants displayed normal RNase IIIa–mediated cleavage of the imperfectly complementary miRNA* strand and tumors with hot-spot mutations were positive for DICER1 expression and had normal levels of mature and processed miRNA, suggesting that these were not loss-of-function mutations. Instead, the recurrent, focal nature of the DICER1 mutations and incomplete loss of DICER1 enzymatic activity observed in nonepithelial ovarian tumors indicate that, in certain cell types, aberrant miRNA processing may be oncogenic. The cell type–specific nature of these mutations is particularly interesting given that epithelial ovarian cancers rarely harbor DICER1 mutations and often exhibit decreased DICER1 expression. Further research is needed to determine which aspects of DICER1 functional impairment drive tumorigenesis and whether these mutations are present in other cancer types.
Heravi-Moussavi A, Anglesio MS, Cheng SW, Senz J, Yang W, Prentice L, et al. Recurrent somatic DICER1 mutations in nonepithelial ovarian cancers. N Engl J Med 2012;366:234–42.
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