The molecular and gene/miRNA expression profiles of radioiodine resistant papillary thyroid cancer

J Exp Clin Cancer Res. 2020 Nov 16;39(1):245. doi: 10.1186/s13046-020-01757-x.

Abstract

Background: Papillary thyroid cancer (PTC) is the most frequent endocrine tumor. Radioiodine (RAI) treatment is highly effective in these tumors, but up to 60% of metastatic cases become RAI-refractory. Scanty data are available on either the molecular pattern of radioiodine refractory papillary thyroid cancers (PTC) or the mechanisms responsible for RAI resistance.

Methods: We analyzed the molecular profile and gene/miRNA expression in primary PTCs, synchronous and RAI-refractory lymph node metastases (LNMs) in correlation to RAI avidity or refractoriness. We classified patients as RAI+/D+ (RAI uptake/disease persistence), RAI-/D+ (absent RAI uptake/disease persistence), and RAI+/D- (RAI uptake/disease remission), and analyzed the molecular and gene/miRNA profiles, and the expression of thyroid differentiation (TD) related genes.

Results: A different molecular profile according to the RAI class was observed: BRAFV600E cases were more frequent in RAI-/D+ (P = 0.032), and fusion genes in RAI+/D+ cases. RAI+/D- patients were less frequently pTERT mutations positive, and more frequently wild type for the tested mutations/fusions. Expression profiles clearly distinguished PTC from normal thyroid. On the other hand, in refractory cases (RAI+/D+ and RAI-/D+) no distinctive PTC expression patterns were associated with either tissue type, or RAI uptake, but with the driving lesion and BRAF-/RAS-like subtype. Primary tumors and RAI-refractory LNMs with BRAFV600E mutation display transcriptome similarity suggesting that RAI minimally affects the expression profiles of RAI-refractory metastases. Molecular profiles associated with the expression of TPO, SLC26A4 and TD genes, that were found more downregulated in BRAFV600E than in gene fusions tumors.

Conclusions: The present data indicate a different molecular profile in RAI-avid and RAI-refractory metastatic PTCs. Moreover, BRAFV600E tumors displayed reduced differentiation and intrinsic RAI refractoriness, while PTCs with fusion oncogenes are RAI-avid but persistent, suggesting different oncogene-driven mechanisms leading to RAI refractoriness.

Keywords: Gene/miRNA profiles; Oncogenes; Papillary thyroid cancer; Radioiodine refractory; Thyroid.

MeSH terms

  • Adult
  • Female
  • Humans
  • Iodine Radioisotopes / metabolism*
  • Male
  • MicroRNAs / genetics*
  • Middle Aged
  • Retrospective Studies
  • Thyroid Cancer, Papillary / genetics*
  • Thyroid Cancer, Papillary / pathology
  • Transcriptome / genetics*

Substances

  • Iodine Radioisotopes
  • MicroRNAs