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The molecular and gene/miRNA expression profiles of radioiodine resistant papillary thyroid cancer
Carla Colombo1,2, Emanuela Minna3, Chiara Gargiuli4
1Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Milan, Italy.
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.
Insights
Papillary thyroid cancer (PTC) molecular profiles differ based on radioiodine (RAI) avidity. BRAF V600E mutations indicate reduced differentiation and intrinsic RAI refractoriness, while fusion oncogenes suggest different mechanisms for RAI resistance.
Area of Science:
- Oncology
- Molecular Biology
- Endocrinology
Background:
- Papillary thyroid cancer (PTC) is the most common endocrine malignancy.
- Radioiodine (RAI) treatment is effective but up to 60% of metastatic PTC cases become RAI-refractory.
- Limited data exist on the molecular characteristics of RAI-refractory PTC and the mechanisms of RAI resistance.
Purpose of the Study:
- To investigate the molecular profiles of RAI-avid versus RAI-refractory metastatic PTC.
- To correlate molecular patterns with RAI uptake and treatment response.
- To elucidate mechanisms of RAI resistance in PTC.
Main Methods:
- Analysis of molecular profiles, gene/miRNA expression in primary PTCs and lymph node metastases (LNMs).
- Classification of patients based on RAI uptake and disease status (RAI+/D+, RAI-/D+, RAI+/D-).
- Assessment of thyroid differentiation (TD) gene expression in relation to molecular subtypes and RAI refractoriness.
Main Results:
- Distinct molecular profiles were observed between RAI-avid and RAI-refractory PTC.
- BRAF V600E mutations were more frequent in RAI-refractory cases (RAI-/D+).
- Fusion oncogenes were associated with RAI-avid but persistent disease (RAI+/D+).
- BRAF V600E-mutated tumors showed reduced expression of TD genes (TPO, SLC26A4) compared to fusion-driven tumors.
- Transcriptome profiles of primary tumors and RAI-refractory LNMs with BRAF V600E were similar, indicating minimal impact of RAI on refractory metastases.
Conclusions:
- RAI-refractory and RAI-avid metastatic PTC exhibit different molecular signatures.
- BRAF V600E-driven PTC demonstrates intrinsic RAI refractoriness due to reduced differentiation.
- Fusion oncogene-driven PTC presents with RAI avidity but persistence, suggesting alternative resistance mechanisms.
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