Age-Associated Alterations in Cytokine and Extracellular Matrix Remodeling in the Papillary Thyroid Cancer Tumor Microenvironment.

Abstract

Age related changes in the tumor microenvironment (TME) may contribute to cancer progression in older adults. Changes in gene expression with age were analyzed to identify differences in cytokine activity and the extracellular matrix (ECM) in papillary thyroid cancer (PTC). RNA sequencing data of PTC samples were obtained from The Cancer Genome Atlas (TCGA) and divided into four groups: G1 (22-55 years), G2 (55-64 years), G3 (65-74 years), and G4 (≥ 75 years). Disease stages were defined as local (T₁-₃N₀M₀), nodal (T_1-3N_1abM₀), and advanced (T₄N_XM_0-1). Differentially expressed genes (DEGs) identified from DESeq2 RNA-seq analysis were subjected to gene set enrichment analysis (GSEA) and ingenuity pathway analysis (IPA). Overall, 476 PTC samples were retrieved: G1 (n = 329), G2 (n = 71), G3 (n = 49), and G4 (n = 27). Advanced disease occurred more frequently in older patients (2% in G1 versus 10% in G4, p < 0.0001). Comparing G1 versus G2, G1 versus G3, and G1 versus G4 identified 179, 153, and 254 DEGs, respectively (p_adj < 0.01). GSEA identified 23 ECM-associated DEGs and 11 cytokine receptor binding-associated DEGs that showed increasing transcription from G1 to G4. A subgroup analysis performed on only patients with conventional PTC found a larger number of DEGs from G1 to G4 than in the overall cohort (85% versus 73%, respectively). Expression of genes associated with the ECM and cytokine receptor binding changed significantly with advanced age, suggesting that age related changes in the TME may contribute to cancer progression.