Gene expression profiling associated with the progression to poorly differentiated thyroid carcinomas.

Objectives: Despite the high overall survival associated with the majority of thyroid tumours, poorly differentiated (PDTC) neoplasia represent a phenotype which may have an aggressive behaviour, often with a fatal outcome. Although the molecular pathogenesis of these carcinomas is still controversial, previous findings suggest a continuum of dedifferentiation from well-differentiated carcinomas (WDTC) to PDTC. To characterise the molecular mechanisms involved in such progression and identify novel therapeutical targets, we compared the genome-wide expression of normal thyroid tissues, WDTC and PDTC cases.Methods: Gene expression profiles of normal thyroid tissues and 24 tumour cases – 7 classic papillary (cPTC), 8 follicular variants of papillary (fvPTC), 4 follicular (FTC) thyroid carcinomas and 5 PDTC – were assessed using the GeneChip HG-U133 Plus 2.0 Array, and correlated with RAS and BRAF mutations, and with RET/PTC1,-2,-3 and PAX8-PPARG rearrangements. Selected genes were further confirmed by quantitative RT-PCR in an independent set of 28 tumours.Results: Hierarchical clustering and principal components analysis showed that distinct profiles separated FTC from other histotypes (PTC and PDTC). Gene expression similarity was higher between PDTC and fvPTC, particularly for tumours harbouring RAS gene mutations. PDTC presented molecular signatures related to cell cycle and proliferation, poor prognosis, mitotic spindle assembly checkpoint and cellular adhesion. Compared to normal tissues, PTC had 307/494 (60%) genes over-expressed, whereas FTC had 137/171 (80%) genes under-expressed. Nonetheless, the highest proportion of under-expression (92/107; 86%) was found in PDTC, suggesting that gene down-regulation is involved in tumour dedifferentiation. The validated genes were significantly deregulated in PDTC samples and also in PDTC cell lines, compared to normal tissues.Conclusions: Our findings suggest that fvPTC, particularly the cases with RAS mutation, are potential precursors of PDTC. The genes confirmed by quantitative RT-PCR have essential roles in DNA methylation or in cell invasion, and so have potential therapeutic uses.