Characterization of microRNA Expression in Medullary Thyroid Carcinoma
Jena Hudson, Eric Duncavage, Samuel Wells, Anna Tamburrino, Paolo Salerno, Liqiang Xi, Mark Raffeld, Jeffrey Moley, Rebecca Chernock. Washington University School of Medicine, St Louis, MO; National Cancer Institute, Bethesda, MD
Background: MicroRNAs (miRNAs) are a primordial mechanism of gene expression control that appear to be crucial to cellular development. Recent evidence suggests that differential expression of miRNAs may play an important role in tumor development. Further, expression of certain miRNAs has been associated with tumor prognosis and may be good targets for future therapies. Approximately 25% of medullary thyroid carcinomas (MTCs) are hereditary and harbor germline activating mutations in the RET gene. Somatic RET mutations are also seen in roughly 50% of sporadic MTCs. We sought to determine the role of miRNA expression in MTC.
Design: DNA and RNA were extracted from formalin-fixed paraffin-embedded tissue blocks of 15 MTCs [10 with RET mutations (5 with M918T mutation) and 5 without RET mutations] and 5 non-tumor thyroids. Three of the RET mutated tumors were from patients with hereditary MTC (all multiple endocrine neoplasia type 2A). Targeted analysis of RET mutations in exons 10, 11, and 13-16 was performed by pyrosequencing. MiRNA expression was then quantitated by Real Time PCR using the ABI OpenArray miRNA assay that included over 800 miRNAs. The resulting data were normalized to averaged RNU48 expression for each case.
Results: Compared to normal thyroid, expression of miR-497 (p=0.007), miR-345 (p=0.012), miR-223 (p=0.013) and miR19b-1 (p=0.036) were significantly lower in MTC (both hereditary and sporadic forms). Within MTCs, expression of miR-193b (p=0.011), miR-125a-3p (p=0.015) and miR-10a (p=0.018) were significantly higher in RET negative versus RET positive MTC. Among RET mutated MTCs, miR-149 (p=0.027) and miR-29c (p=0.034) expression were significantly lower in cases with M918T RET mutations. Interestingly many of these miRNAs have been implicated in other malignancies.
Conclusions: Using quantitative real time PCR we identified several miRNAs that showed significant changes in expression when comparing MTC to normal thyroid, RET-mutated to non-mutated cases, and RET M918T-mutations to other RET mutations. These data suggest that the biology of MTC may depend on altered miRNA expression. Further, there appears to be differences in miRNA expression profiles between RET-mutated and non-mutated MTC, suggesting that RET-mutated MTC may result in alterations to different biologic pathways.
Monday, March 19, 2012 9:30 AM
Poster Session I Stowell-Orbison/Surgical Pathology/Autopsy Awards Poster Session # 96, Monday Morning