Glucagon-like peptide-1 receptor (GLP-1R) overexpression defines a distinct immunogenetic subset in primary and...

The surge in prescribing glucagon-like peptide-1 receptor agonists (GLP-1 RAs) for diabetes and weight management highlights a pressing need to characterize their associated risks. All GLP-1 RAs include an FDA boxed warning for increased risk of development of medullary thyroid carcinoma (MTC) based on early murine studies. However, clinical evidence remains conflicting and highly debated, highlighting the importance of comprehensively characterizing GLP-1R expression in both primary and metastatic thyroid cancers.

We leveraged transcriptomic data from The Cancer Genome Atlas (TCGA) from 11,160 patients across 33 cancer types to comparatively analyze GLP-1R transcriptomic expression across normal, primary, and metastatic tissues. We also performed flow cytometric analysis on primary and metastatic medullary and papillary thyroid carcinomas (PCT) to quantify differential GLP-1R protein expression levels.

Strikingly, metastatic PTC displayed the highest median GLP-1R mRNA expression among all TCGA cancers. This finding was supported by flow cytometry of patient tumor samples, which confirmed elevated GLP-1R protein expression in both PTC and MTC metastatic tissues as compared to their respective primary tumors. Further, GLP-1R expression levels stratified TCGA thyroid cancers into unique immunogenetic transcriptional profiles. Tumors with high GLP-1R expression were notably associated with downregulated immune pathway activity and decreased immune cell infiltration.

These findings identify a subset of thyroid carcinomas with high GLP-1R expression, most pronounced in metastatic disease, which are accompanied by distinct genetic and immunological profiles. As GLP-1R agonist therapies continue to expand in clinical use, further investigation is warranted to determine the oncogenic implications of this overexpression for thyroid cancer.