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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 novel anti-DTC agents. The purpose of this study is to establish a comprehensive PCD relevant signature in genomic and transcriptomic backgrounds to predict susceptible genes and the checkpoints of immunotherapy in DTC patients. Methods Based on 14 kinds of PCD patterns, we leveraged Summary-data-based Mendelian randomization (SMR) analysis, integrating expression quantitative trait loci (eQTL) from blood and thyroid to identify hub genes causally associated with the pathogenesis of DTC preliminarily. ScRNA-seq analysis was linked to individual genetic variations to reveal cell specificity in peripheral blood mononuclear cells (PBMCs) and tumor microenvironment, respectively. Furthermore, we analyzed the degree of immune infiltration and clinical correlation with TNM stages. Results SMR analysis suggested that 6 genes were replicated in both blood and thyroid tissues, which were associated with 3 distinct PCD patterns: Apoptosis (NFATC4, RPS3 and TM2D1), Lysosome-dependent cell death (CTNS and GCC2), Autophagy (TPCN2). Besides, scRNA-seq and expression analysis found the expression of RPS3 in the old (> 65 years old) were significantly lower than those in young. And it was worth noting that the expression levels of CTNS, GCC2, TM2D1 and TPCN2 gradually decreased with the increase of T stage. Conclusions This study uncovered several PCD related genes serving important roles in protecting against the development of DTC. Intensive transcriptome analysis provided comprehensive bioinformatic basis for further investigations to explore the detailed regulatory mechanisms, which might open up new therapeutic targets among patients with DTC.
Zhang et al. (Tue,) studied this question.
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