microRNA profiles in familial and sporadic medullary thyroid carcinoma: preliminary relationships with RET status and outcome.
ABSTRACT Background: microRNAs (miRNAs) are involved in the pathogenesis of human cancers, including medullary thyroid carcinomas (MTC). The aim of this study was to test the hypothesis that different miRNA profiles are related to RET status and prognosis in hereditary (hMTC) and sporadic (sMTC) MTC patients. Methods: We analyzed the expression of nine miRNAs (miR-21, miR-127, miR-154, miR-224, miR-323, miR-370, miR-9*, miR-183, and miR-375) by quantitative RT-PCR in 34 cases of sMTC, 6 cases of hMTC and 2 cases of C-cell hyperplasia (CCH). We also analyzed the immunohistochemical expression of PDCD4, a miR-21 gene target. sMTC (n=34) were genotyped for somatic RET and RAS mutations. Disease status was defined on the basis of the concentration of serum calcitonin at the latest follow-up and other parameters as indicated in the results. Results: MTC and CCH were both characterized by a significant overexpression of the whole set of miRNAs (the increase being 4.2-fold for miR-21, 6.7-fold for miR-127, 8.8-fold for miR-154, 6.6-fold for miR-224, 5.8-fold for miR-323 and 6.1-fold for miR-370, 13-fold for miR-9*, 6.7-fold for miR-183 and 10.1 for miR-375, p<0.0001). PDCD4 expression was significantly down-regulated in MTC samples, consistent with miR-21 upregulation. Significantly lower miR-127 levels were observed in sMTC carrying somatic RET mutations in comparison to sMTC carrying a wild-type RET. In sporadic and familial MTC, the miR-224 upregulation correlated with the absence of node metastases, lower stages at diagnosis, and with biochemical cure during follow-up. Conclusions: miRNAs are significantly dysregulated in MTC, and this dysregulation is probably an early event in C-cell carcinogenesis. miR-224 upregulation could represent a prognostic biomarker associated with a better outcome in MTC patients.
SourceAvailable from: Marc Philippe Pusztaszeri[Show abstract] [Hide abstract]
ABSTRACT: Medullary thyroid carcinoma (MTC) accounts for only 5% to 10% of all thyroid carcinomas, but it is the most aggressive form of well-differentiated thyroid carcinoma, being responsible for 8% to 15% of all thyroid cancer-related deaths. MTC is frequently diagnosed at a locally advanced or metastatic stage, and 10-year survival rates in these cases are <20%. Fine-needle aspiration biopsy of the thyroid gland is an accurate method to diagnose MTC, having a high sensitivity and specificity. The cytologic features of MTC are characteristic and the cytologic diagnosis of classic MTC is often straightforward, especially when combined with immunocytochemistry. However, because of its morphologic heterogeneity and overlap with other tumors, the differential diagnosis of MTC on cytology and on histology is broad with several potential pitfalls. Significant advances have been made over the last decade in understanding MTC. This concerns mainly the early detection of MTC, especially in familial forms (eg, multiple endocrine neoplasia type 2), and the identification of key molecular pathways and alterations which now offer promising targets for specific therapies in progressive MTC cases. Genetic testing (eg, RET mutation) has allowed for early detection in asymptomatic carriers and high-risk patients, with prophylactic thyroidectomy often being curative. Targeted therapies with multityrosine-kinase inhibitors (eg, vandetanib or cabozantinib) have emerged as promising new treatments for recurrent or metastatic MTC. In this review article, we discuss the cytologic features of MTC and its variants, its differential diagnosis, the role of ancillary studies, and the salient molecular features of MTC.Advances in Anatomic Pathology 01/2014; 21(1):31-40. · 3.10 Impact Factor
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ABSTRACT: Our understanding of the molecular pathology of thyroid cancer has progressed significantly. It is now apparent that thyroid tumors show a very good correlation between genotype and phenotype, a correlation that is much stronger than that observed in tumors of many other organs. Activation of classic oncogenes (BRAF, RAS, RET) activate MAPK signalling. Other pathways like the PI3K/PTEN/AKT cascade are also active in many thyroid tumors. The analysis of molecular profiles is generating data that can be applied to improve patient management. The common occurrence of thyroid nodules in the general population and the widespread use of fine needle aspiration for the preoperative diagnosis of thyroid nodules creates an unprecedented opportunity to apply what we have learnt from the molecular alterations of thyroid cancer to the clinical arena.Frontiers in bioscience (Elite edition) 01/2014; 6:1-14.
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ABSTRACT: MicroRNAs (miRNAs) have emerged as a class of powerful gene expression regulators. Acting at the post-transcriptional level, miRNAs modulate the expression of at least one-third of the mRNAs that are encoded by the human genome. The expression of a single gene can be regulated by several miRNAs, and every miRNA has more than one target gene. Thus, the miRNA regulatory circuit, which affects essential cellular functions, is of enormous complexity. Moreover, a fundamental role for miRNAs has been determined in the onset and progression of human cancers. Here, we summarize the main alterations in miRNA expression that have been identified in thyroid neoplasias and examine the mechanisms through which miRNA deregulation might promote thyroid cell transformation. We also discuss how the emerging knowledge on miRNA deregulation could be harnessed for the diagnosis and treatment of thyroid neoplasias.Nature Reviews Endocrinology 11/2013; DOI:10.1038/nrendo.2013.223 · 12.96 Impact Factor