Dataset Information

Molecular classification of thyroid lesions by combined testing for miRNA gene expression and somatic gene alterations.

ABSTRACT: 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?

SUBMITTER: Wylie D

PROVIDER: S-EPMC4907059 | biostudies-literature | 2016 Apr

REPOSITORIES: biostudies-literature

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Molecular classification of thyroid lesions by combined testing for miRNA gene expression and somatic gene alterations.

Wylie Dennis D Beaudenon-Huibregtse Sylvie S Haynes Brian C BC Giordano Thomas J TJ Labourier Emmanuel E

The journal of pathology. Clinical research 20160208 2

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) ...[more]

PMID: 27499919

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Project description:BACKGROUND:Thyroid nodules are less common in pediatric patients (i.e., those ?18 years) than they are in adults. The Bethesda System for Reporting Thyroid Cytopathology allows for individual risk stratification, but a significant number of nodules are indeterminate. Incorporating gene mutation panels and gene expression classifiers may aid in preoperative diagnosis. The overall aim of this study was to assess the prevalence of oncogene alterations in a representative pediatric population and across a broad-spectrum of thyroid tumor diagnoses. METHODS:This was a retrospective cross-sectional evaluation of 115 archived samples, including: 47 benign (29 follicular adenoma, 11 diffuse hyperplasia, four thyroiditis, and three multinodular goiter), six follicular thyroid carcinomas (FTC), 24 follicular variant of papillary thyroid carcinomas (fvPTC), 27 classic variant of PTC (cPTC), eight diffuse sclerosing variant of PTC (dsvPTC), and three other PTC. Molecular testing was performed by multiplex qualitative polymerase chain reaction followed by bead array cytometry. Oncogene results were analyzed for association with age, sex, histology, lymph node metastasis, and intrathyroidal spread. RESULTS:A mutation in one of the 17 molecular markers evaluated was found in: 2/6 (33%) FTC, 8/24 (33%) fvPTC, 17/27 (63%) cPTC, and 4/8 (50%) dsvPTC. Mutations in RAS or PAX8/PPARG were exclusive to FTC and fvPTC. BRAF was the most common mutation in cPTC (12/17; 71%), and RET/PTC was the only mutation associated with dsvPTC. Overall, a mutation was found in 32/68 (47%) malignant specimens, with a single follicular adenoma positive for PAX8/PPARG. The relative distribution of gene alterations in pediatric lesions was similar to adults. The presence of a BRAF mutation in pediatric cPTC did not predict a more invasive phenotype. CONCLUSIONS:Of 33 nodules with genetic alterations, 32 were malignant. Mutations in RAS were most frequently associated with FTC, RET/PTC rearrangements with dsvPTC, and invasive fvPTC, and BRAF with cPTC. These results suggest a clinical role for mutational analysis of pediatric nodules to guide the surgical approach.

Project description:BACKGROUND:Papillary thyroid cancer (PTC) is the most frequent endocrine tumor. Radioiodine (RAI) treatment is highly effective in these tumors, but up to 60% of metastatic cases become RAI-refractory. Scanty data are available on either the molecular pattern of radioiodine refractory papillary thyroid cancers (PTC) or the mechanisms responsible for RAI resistance. METHODS:We analyzed the molecular profile and gene/miRNA expression in primary PTCs, synchronous and RAI-refractory lymph node metastases (LNMs) in correlation to RAI avidity or refractoriness. We classified patients as RAI+/D+ (RAI uptake/disease persistence), RAI-/D+ (absent RAI uptake/disease persistence), and RAI+/D- (RAI uptake/disease remission), and analyzed the molecular and gene/miRNA profiles, and the expression of thyroid differentiation (TD) related genes. RESULTS:A different molecular profile according to the RAI class was observed: BRAFV600E cases were more frequent in RAI-/D+ (P?=?0.032), and fusion genes in RAI+/D+ cases. RAI+/D- patients were less frequently pTERT mutations positive, and more frequently wild type for the tested mutations/fusions. Expression profiles clearly distinguished PTC from normal thyroid. On the other hand, in refractory cases (RAI+/D+ and RAI-/D+) no distinctive PTC expression patterns were associated with either tissue type, or RAI uptake, but with the driving lesion and BRAF-/RAS-like subtype. Primary tumors and RAI-refractory LNMs with BRAFV600E mutation display transcriptome similarity suggesting that RAI minimally affects the expression profiles of RAI-refractory metastases. Molecular profiles associated with the expression of TPO, SLC26A4 and TD genes, that were found more downregulated in BRAFV600E than in gene fusions tumors. CONCLUSIONS:The present data indicate a different molecular profile in RAI-avid and RAI-refractory metastatic PTCs. Moreover, BRAFV600E tumors displayed reduced differentiation and intrinsic RAI refractoriness, while PTCs with fusion oncogenes are RAI-avid but persistent, suggesting different oncogene-driven mechanisms leading to RAI refractoriness.

Dataset Information

Molecular classification of thyroid lesions by combined testing for miRNA gene expression and somatic gene alterations.

Publications

Molecular classification of thyroid lesions by combined testing for miRNA gene expression and somatic gene alterations.

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