Abstract for presentation at 11th International Congress of Human Genetics

Papillary Thyroid Carcinoma (PTC) is the most common thyroid malignancy, with an incidence of ~22,000 cases in 2004 in the U.S. Incidence is increasing, with a global estimate of half a million new cases this year. PTC is found in a variety of morphological variants, usually grows slowly and is clinically indolent, although rare, aggressive forms, with local invasion or distant metastases occur. The primary aim of this study was generate an overview of molecular markers of malignancy in PTC with a view to identifying discriminators between common genetic triggers (ret/PTC-1 and BRAF mutation).
Design: To compare the effects of oncogenic BRAF and ret/PTC-1 in thyroid carcinoma, gene expression profiles for a panel of thyroid cell lines were compared using the 1700 human expression profiling system from Applied Biosystems. The panel included cell lines characteristic of various papillary and anaplastic thyroid carcinomas harbouring BRAF /ret/PTC-1 mutations and a normal thyroid cell line. In addition, the normal cell line was transfected to create modified cell lines expressing V600EBRAF and chimeric ret/PTC-1. Further, this cell line matrix was interrogated using Applied Biosystems TaqMan MicroRNA Assays Human Panel comprising157 miRNAs to elucidate the miRNA profiles associated with particular molecular triggers of PTC.
Results: Genes found to be differentially expressed were those involved in cell structure, motility, and the extracellular matrix. Genes involved in the MAPK signalling pathway, oncogenesis and transcription regulation where shown to be upregulated. Several cell cycle regulators were down-regulated. Escape of apoptosis was also a consistent theme with its inducers and inhibitors frequently found to be down- and up-regulated respectively. Discrete miRNA signatures were found contingent on the primary genetic aberration (ret/PTC-1 or BRAT mut) present in the cell line matrix.
Conclusion: ret/PTC and BRAF mutations play a significant role in the pathogenesis of PTC. The molecular pathogenesis of this disease remains poorly characterized. There is a need to identify significant biomarkers of malignancy to help in diagnosis and treatment. The data generated in this study has highlighted several key cellular pathways and genes that are significantly associated with alternate tumourigenic triggers in the context of PTC. Specific miRNA patterns associate with ret/PTC or BRAF status and their predicted protein targets corroborate the expression microarray data.