N. G. Nicolson1, J. Paulsson2, C. Juhlin2, R. Korah1, T. Carling1 1Yale University School Of Medicine,Department Of Surgery,New Haven, CT, USA 2Karolinska Institute,Solna, STOCKHOLM COUNTY, Sweden
Introduction: Follicular thyroid cancer (FTC) is generally indolent with low risk of recurrence or death, but some cases are of encapsulated angio-invasive (eaFTC) or widely invasive (wiFTC) histological subtypes, portending a significantly worse prognosis. The mechanism and associated biomarkers of this invasive behavior have not been fully elucidated.
Methods: Tissue samples including minimally invasive FTC (miFTC), eaFTC, and wiFTC tumors, as well as histologically normal thyroid adjacent to benign follicular adenomas, were selected from a cohort (n=21) of thyroid tumor patients. Histology was confirmed by experienced endocrine pathologists to designate the invasiveness of each sample as described in the 2017 WHO Guidelines. Total RNA was isolated, reverse transcribed, and subjected to a quantitative PCR array containing 84 transcription factor probes, with relative expression levels determined by a modified Livak method. Genes differentially expressed in invasive FTC were determined. In silico network analysis was performed to highlight involved signaling networks. Immunohistochemistry was performed to assess spatial expression patterns of selected transcription factors.
Results: Of the 84 transcription factors studied, 30 were differentially expressed between FTC and normal, or between invasive subtypes of FTC. E2F transcription factor 1 (E2F1), a ubiquitous transcription factor, was over-expressed in all 3 FTC subtypes (p<0.01, Figure 1). Specificity factor 1 (SP1), previously shown to modulate invasion in breast, prostate, and gastric cancers, was differentially expressed in eaFTC and wiFTC (p<0.05, Figure 1). Transcription factor 7-like 2 (TCF7L2), an established inducer of epithelial-to-mesenchymal transition and associated cancer invasion, was significantly upregulated in widely invasive tumors specifically (p<0.05, Figure 1). Thirteen transcription factors were differentially expressed in eaFTC and wiFTC compared to miFTC, and network interaction analysis suggested a role for Wnt signaling and associated networks in the invasive phenotype. Immunohistochemistry revealed differential expression of Yin and Yang 1 protein (YY1) and Myc-Associated Factor X (MAX) along the tumor invasive front relative to the central tumor, suggesting that invasiveness may be a local phenomenon rather than a property of the tumor at large.
Conclusion: Invasive FTC is rare but has a high risk of recurrence and death relative to minimally invasive FTC. This study identifies differential transcription factor expression associated with invasive subtypes of FTC and identifies dysregulated signaling pathways by investigating transcriptional regulation. Our study lays the groundwork for novel therapies targeting invasion pathways in FTC.
