Abstract
BackgroundPapillary 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.MethodsWe 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.ResultsA 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.ConclusionsThe 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.
Highlights
Papillary thyroid cancer (PTC) is the most frequent endocrine tumor
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
The molecular profile of PTCs correlated to radioiodine resistance Analysis in 70 primary PTCs The molecular profile was different in the 3 groups of patients: BRAFV600E was significantly more frequent in RAI−/D+ group (66%) compared with RAI+/D+ (35%) and RAI+/D- (33%) groups (P = 0.032)
Summary
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. Radioactive iodine (RAI) therapy is a very effective treatment, significantly increasing the life expectancy of differentiated thyroid cancer (DTC) patients [1]. According to American Thyroid Association (ATA) Guidelines [3], RAI-refractory DTCs are identified by: a) presence of malignant/metastatic tissue that does not ever concentrate RAI, b) presence of tumor tissue that loses the ability to concentrate RAI after previous evidence of RAI-avid disease, c) RAI uptake in some lesions but not in others, and d) metastatic disease that progresses despite significant concentration of RAI. No difference either in NIS or in other thyroid differentiation genes was found in PTC with or without RET/PTC rearrangements [7], in accordance with the notion that these tumors rarely progress to aggressive or undifferentiated carcinomas [8]
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