Genome-wide association and expression analyses of programmed cell death associated genes provide novel insight into therapeutic target in differentiated thyroid cancer

Abstract BACKGROUND The incidence of differentiated thyroid cancer (DTC) has been increasing in recent years with high risk of recurrence and metastasis. Inducing programmed cell death (PCD) is one of the most promising therapy in the development of anti-DTC agents. However, which genes play the key roles in DTC remain unclear. METHODS Based on 14 kinds of PCD patterns, we leveraged Summary-data-based Mendelian randomization (SMR) analysis, integrating DTC GWAS (Cases comprised of 649 patients had histological proven) with expression quantitative trait loci (eQTL) from blood in eQTLGen and verifed in thyroid tissues of GTExV8 to explore the causality between different PCD genes and DTC in genomic and transcriptomic backgrounds. scRNA-seq analysis was linked to individual genetic variation to reveal cell specificity in peripheral blood mononuclear cells (PBMCs) and tumor microenvironment, respectively. Furthermore, we also analyzed the relationship of susceptibility genes and immune infiltration and clinicl correlation with the pathological stages. RESULTS The results suggested that 55 PCD genes in blood exhibited association with DTC, 48 of which were enriched in PBMCs. 13 genes were found in thyroid tissue cis-eQTL, 12 of which could be verified in tumor microenvironment. Among these, 6 genes consistently replicated in both blood and thyroid tissues were proposed preferentially. These genes were associated with 3 distinct PCD patterns: Apoptosis (NFATC4, RPS3 and TM2D1), Lysosome-dependent cell death (CTNS and GCC2), Autophagy (TPCN2). Besides, the expression levels of RRPS3 and TM2D1 genes in elderly (> 65 years old) patients with thyroid cancer were significantly lower than those in young. And it was worth noting that the expression levels of CTNS, GCC2, TM2D1 and TPCN2 genes gradually decreased with the increase of T stage. CONCLUSIONS This study uncovered several PCD related genes protecting against the development of DTC. These results provide a basis for further exploring the regulatory mechanisms of PCD on DTC, which might open up new therapy target for DTC based on inducing in programmed cell death.