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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 carcinoma (MTC). The aim of this study was to test the hypothesis that different miRNA profiles are related to RET status and prognosis in patients with hereditary MTC (hMTC) and sporadic MTC (sMTC). 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 real-time-polymerase chain reaction 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, an miR-21 gene target. sMTC (n=34) was 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, 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 downregulated 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 sMTC 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.

SUBMITTER: Mian C

PROVIDER: S-EPMC3429275 | biostudies-literature | 2012 Sep

REPOSITORIES: biostudies-literature

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MicroRNA profiles in familial and sporadic medullary thyroid carcinoma: preliminary relationships with RET status and outcome.

Mian Caterina C Pennelli Gianmaria G Fassan Matteo M Balistreri Mariangela M Barollo Susi S Cavedon Elisabetta E Galuppini Francesca F Pizzi Marco M Vianello Federica F Pelizzo Maria Rosa MR Girelli Maria Elisa ME Rugge Massimo M Opocher Giuseppe G

Thyroid : official journal of the American Thyroid Association 20120629 9

<h4>Background</h4>MicroRNAs (miRNAs) are involved in the pathogenesis of human cancers, including medullary thyroid carcinoma (MTC). The aim of this study was to test the hypothesis that different miRNA profiles are related to RET status and prognosis in patients with hereditary MTC (hMTC) and sporadic MTC (sMTC).<h4>Methods</h4>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 real-time-polymerase chain ...[more]

PMID: 22747440

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Project description:BackgroundThe cyclin-dependent-kinase inhibitors (CDKN)/retinoblastoma (RB1) pathway has been implicated as having a role in medullary thyroid carcinoma (MTC) tumorigenesis. CDKN2C loss has been associated with RET-mediated MTC in humans but with minimal phenotypic correlation provided. The objective of this study was to evaluate the association between tumor RET mutation status, CDKN2C loss, and aggressiveness of MTC in a cohort of patients with sporadic disease.MethodsTumors from patients with sporadic MTC treated at a single institution were evaluated for somatic RETM918T mutation and CDKN2C copy number loss. These variables were compared to patient demographics, pathology detail, clinical course, and disease-specific and overall survival.ResultsSixty-two MTC cases with an initial surgery date ranging from 1983 to 2009 met the inclusion criteria, of whom 36 (58%) were male. The median age at initial surgery was 53 years (range 22-81 years). The median tumor size was 30 mm (range 6-145 mm) with 29 (57%) possessing extrathyroidal extension. Nodal and/or distant metastasis at presentation was found in 47/60 (78%) and 12/61 (20%) patients, respectively. Median follow-up time was 10.5 years (range 1.1-27.8 years) for the censored observations. The presence of CDKN2C loss was associated with worse M stage and overall AJCC stage. Median overall survival of patients with versus without CDKN2C loss was 4.14 [confidence interval (CI) 1.93-NA] versus 18.27 [CI 17.24-NA] years (p < 0.0001). Median overall survival of patients with a combined somatic RETM918T mutation and CDKN2C loss versus no somatic RETM918T mutation and CDKN2C loss versus somatic RETM918T mutation and CDKN2C 2N versus no somatic RETM918T mutation and CDKN2C 2N was 2.38 [CI 1.67-NA] years versus 10.81 [CI 2.46-NA] versus 17.24 [CI 9.82-NA] versus not reached [CI 13.46-NA] years (p < 0.0001).ConclusionsThe detection of somatic CDKN2C loss is associated with the presence of distant metastasis at presentation as well decreased overall survival, a relationship enhanced by concomitant RETM918T mutation. Further defining the genes involved in the progression of metastatic MTC will be an important step toward identifying pathways of disease progression and new therapeutic targets.

Dataset Information

MicroRNA profiles in familial and sporadic medullary thyroid carcinoma: preliminary relationships with RET status and outcome.

Publications

MicroRNA profiles in familial and sporadic medullary thyroid carcinoma: preliminary relationships with RET status and outcome.

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