Thyroid follicular adenomas and carcinomas: molecular profiling provides evidence for a continuous evolution

Abstract

Non-autonomous thyroid nodules are common in the general population with a proportion found to be cancerous. A current challenge in the field is to be able to distinguish benign adenoma (FA) from preoperatively malignant thyroid follicular carcinoma (FTC), which are very similar both histologically and genetically. One controversial issue, which is currently not understood, is whether both tumor types represent different molecular entities or rather a biological continuum.To gain a better insight into FA and FTC tumorigenesis, we defined their molecular profiles by mRNA and miRNA microarray. Expression data were analyzed, validated by qRT-PCR and compared with previously published data sets.The majority of deregulated mRNAs were common between FA and FTC and were downregulated, however FTC showed additional deregulated mRNA. Both types of tumors share deregulated pathways, molecular functions and biological processes. The additional deregulations in FTC include the lipid transport process that may be involved in tumor progression. The strongest candidate genes which may be able to discriminate follicular adenomas and carcinomas, CRABP1, FABP4 and HMGA2, were validated in independent samples by qRT-PCR and immunohistochemistry. However, they were not able to adequately classify FA or FTC, supporting the notion of continuous evolving tumors, whereby FA and FTC appear to show quantitative rather than qualitative changes. Conversely, miRNA expression profiles showed few dysregulations in FTC, and even fewer in FA, suggesting that miRNA play a minor, if any, role in tumor progression.

Association between DNA methylation profile and malignancy in follicular-patterned thyroid neoplasms

“…By focusing on FTC-associated DMCpGs, we found that, in FTAs, their methylation levels distribute in an intermediate position between normal samples and FTCs. As recently demonstrated by global expression profiling (Dom et al 2018), these findings are consistent with the possibility that FTA may represent a biological intermediate between normal tissue and FTC (Arora et al 2008, Sobrinho-Simões et al 2011, Giordano 2018.…”

“…FTA and FTC share similar genetic lesions suggesting that these two neoplams may be representative of different steps of a common biological process (Zhu et al 2003, Arora et al 2008, Fagin & Wells 2016, Jung et al 2016, Yoo et al 2016, Giordano 2018. Recent gene expression profiling by mRNA and miRNA arrays has confirmed this hypothesis (Dom et al 2018). The driver mutations that are more frequently detected in FTC involve missense mutations in the H/K/N-RAS genes (up to 53% of the cases) and, less commonly, the PAX8-PPARG fusion (19-63% of the cases).…”

Diagnostic performance of HMGA2 gene expression for differentiation of malignant thyroid nodules: A systematic review and meta‐analysis

“…It was well established that accurate diagnosis of FTC should be needed the entire histologic examination of the fibrous capsule and vasculature for detection of invasion . In view of particular challenge in preoperative accurate diagnosis of follicular neoplasm, HMGA2 expression could be useful in the differential diagnosis of follicular neoplasm . However, previous studies which were included in the current meta‐analysis were mostly retrospective studies and small sample size of FTC.…”

“…2,4 In view of particular challenge in preoperative accurate diagnosis of follicular neoplasm, HMGA2 expression could be useful in the differential diagnosis of follicular neoplasm. [15][16][17][18][19][20][21]39 However, previous studies which were included in the current metaanalysis were mostly retrospective studies and small sample size of FTC. Therefore, further prospective studies with large sample size and combination of other candidate molecular markers should be required.…”

Current and future markers for the diagnosis of thyroid cancer

“…In addition to gene expression signature, miRNA profiling was further developed as an important main for the diagnosis of thyroid carcinomas [38]. The mechanisms of miRNA implication in cancer development are linked to the downregulation of tumor suppressor genes or the upregulation of oncogenes.…”