Transcription Factor Profiling Identifies Spatially Heterogenous Mediators of Follicular Thyroid Cancer Invasion

Norman G Nicolson,Tobias Carling,C Christofer Juhlin,Johan O Paulsson,Reju Korah

doi:10.1007/s12022-020-09651-0

Norman G Nicolson, Tobias Carling + Show 3 more

Open Access

https://doi.org/10.1007/s12022-020-09651-0

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Abstract

While minimally invasive follicular thyroid cancer (miFTC) generally has low risk of recurrence or death, encapsulated angioinvasive (eaFTC) or widely invasive (wiFTC) histological subtypes display significantly worse prognosis. Drivers of invasion are incompletely understood. Therefore, tissue samples including 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, and the gene expression of selected transcription factors was characterized with quantitative PCR. Invasion-relevant spatial expression patterns of selected transcription factors were subsequently characterized with immunohistochemistry. E2F1 was over-expressed in all 3 subtypes (p<0.01). SP1 was differentially expressed in eaFTC and wiFTC compared with normal (p=0.01 and 0.04, respectively). TCF7L2 was significantly upregulated in wiFTC specifically (p<0.05). While these findings were mRNA specific, immunohistochemistry of additional cancer-associated transcription factors revealed differential expression along the tumor invasive front relative to the central tumor, and histone acetylation modulators emerged as putative invasion markers. These findings may have significant implications for the interpretation of bulk gene expression analysis of thyroid tumor samples or for the development of targeted therapeutics for this rare but aggressive thyroid cancer variant.

Highlights

Follicular thyroid cancer (FTC) is the second most common type of well-differentiated thyroid cancer, making up about 10–15% of thyroid cancer diagnosesElectronic supplementary material The online version of this article contains supplementary material, which is available to authorized users.overall [1, 2]
E2F transcription factor 1 (E2F1), a ubiquitous transcription factor associated with cell cycle and proliferation, was over-expressed in all 3 FTC subtypes relative to non-neoplastic thyroid (p
Specificity factor 1 (SP1), previously shown to modulate invasion in breast, prostate, and gastric cancers, was differentially expressed in eaFTC and wiFTC compared with normal (p

Summary

Introduction

In 2017, the World Health Organization released updated histopathological guidelines for FTC, which divided the disease into minimally invasive (miFTC), encapsulated angioinvasive (eaFTC), and widely invasive (wiFTC) subtypes [5] Definitively distinguishing these categories from one another, and even distinguishing benign follicular adenoma from FTC, requires a complete surgical specimen to assess the degree of capsular or vascular invasion, which cannot readily be determined from fineneedle aspiration (FNA) cytology specimens [6]. In light of this limitation, patients with indeterminate cytological findings after FNA are often faced with undergoing so-called diagnostic surgery (usually hemithyroidectomy) to arrive at a final diagnosis, which might in many cases require a return to the operating room for definitive surgery [7]. This has been somewhat successful for papillary thyroid cancer (PTC), the most common well-differentiated thyroid cancer, but less so for FTC [10]

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