Dataset Information

DICER1 somatic mutations strongly impair miRNA processing even in benign thyroid lesions.

ABSTRACT: The alteration of miRNA processing is a driver event in several tumors including thyroid cancer. In particular, somatic DICER1 mutations, reported in follicular-patterned lesions, are shared by benign as well as malignant tumors. In the present study, we investigated the effects of alterations in the miRNA processing genes on the miRNA profile. The study included 19 follicular adenomas (FAs) and 22 follicular variant of papillary thyroid carcinomas (FVPTCs). The mutational status in the hot spot regions of DICER1, DROSHA, TARBP2, DGCR8 and the most commonly affected genes in thyroid tumors was investigated on both tumor and paired normal tissues. The miRNA profile and the mRNA expression levels of DICER1, DROSHA, TARBP2, DGCR8 and XPO5 were also evaluated. Two DICER1 RNase IIIb domain mutations were found in FAs. These lesions presented a considerable loss of 5p miRNAs. Fifteen miRNAs were specifically deregulated in DICER1-mutant lesions compared to FAs and FVPTCs. These miRNAs regulate crucial pathways in cancer such as Hippo, p53 and TGF-beta signalling. DICER1 somatic mutations in the RNase IIIb domain are not specific for malignancy, but the miRNA imbalance that they cause is remarkable, especially with regard to the loss of 5p miRNAs. DICER1-mutant lesions have a characteristic miRNA deregulation, which is different from that of FVPTCs; nevertheless, this impairment is consistent with malignant transformation. Further studies providing the real risk of malignancy associated with DICER1 mutations and the evolution of DICER1-mutant lesions are needed to make them useful in the clinical practice.

SUBMITTER: Poma AM

PROVIDER: S-EPMC6442996 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature

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<i>DICER1</i> somatic mutations strongly impair miRNA processing even in benign thyroid lesions.

Poma Anello Marcello AM Condello Vincenzo V Denaro Maria M Torregrossa Liborio L Elisei Rossella R Vitti Paolo P Basolo Fulvio F

Oncotarget 20190305 19

The alteration of miRNA processing is a driver event in several tumors including thyroid cancer. In particular, somatic <i>DICER1</i> mutations, reported in follicular-patterned lesions, are shared by benign as well as malignant tumors. In the present study, we investigated the effects of alterations in the miRNA processing genes on the miRNA profile. The study included 19 follicular adenomas (FAs) and 22 follicular variant of papillary thyroid carcinomas (FVPTCs). The mutational status in the h ...[more]

PMID: 30956758

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Project description:Multiple molecular markers contribute to the pathogenesis of thyroid cancer and can provide valuable information to improve disease diagnosis and patient management. We performed a comprehensive evaluation of miRNA gene expression in diverse thyroid lesions (n?=?534) and developed predictive models for the classification of thyroid nodules, alone or in combination with genotyping. Expression profiling by reverse transcription-quantitative polymerase chain reaction in surgical specimens (n?=?257) identified specific miRNAs differentially expressed in 17 histopathological categories. Eight supervised machine learning algorithms were trained to discriminate benign from malignant lesions and evaluated for accuracy and robustness. The selected models showed invariant area under the receiver operating characteristic curve (AUC) in cross-validation (0.89), optimal AUC (0.94) in an independent set of preoperative thyroid nodule aspirates (n?=?235), and classified 92% of benign lesions as low risk/negative and 92% of malignant lesions as high risk/positive. Surgical and preoperative specimens were further tested for the presence of 17 validated oncogenic gene alterations in the BRAF, RAS, RET or PAX8 genes. The miRNA-based classifiers complemented and significantly improved the diagnostic performance of the 17-mutation panel (p?<?0.001 for McNemar's tests). In a subset of resected tissues (n?=?54) and in an independent set of thyroid nodules with indeterminate cytology (n?=?42), the optimized ThyraMIR Thyroid miRNA Classifier increased diagnostic sensitivity by 30-39% and correctly classified 100% of benign nodules negative by the 17-mutation panel. In contrast, testing with broad targeted next-generation sequencing panels decreased diagnostic specificity by detecting additional mutations of unknown clinical significance in 19-39% of benign lesions. Our results demonstrate that, independent of mutational status, miRNA expression profiles are strongly associated with altered molecular pathways underlying thyroid tumorigenesis. Combined testing for miRNA gene expression and well-established somatic gene alterations is a novel diagnostic strategy that can improve the preoperative diagnosis and surgical management of patients with indeterminate thyroid nodules.

Dataset Information

DICER1 somatic mutations strongly impair miRNA processing even in benign thyroid lesions.

Publications

<i>DICER1</i> somatic mutations strongly impair miRNA processing even in benign thyroid lesions.

Similar Datasets

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