DataSheet_1_Prognostic and immunomodulatory roles of schizophrenia-associated genes HTR2A, COMT, and PRODH in pan-cancer analysis and glioma survival prediction model.xlsx

BackgroundThe shortened life expectancy in schizophrenia (SCZ) patients may be correlated with most cancers, yet there is heterogeneity in the studies examining these correlations. This study explored the expression of SCZ-related genes (HTR2A, COMT, and PRODH) in pan-cancer analysis. It helped to enhance the mechanistic understanding of the SCZ-cancer relationship and their immune mechanisms at the genetic level. Additionally, this study established a survival prediction model for glioblastoma and low-grade glioma (GBMLGG).
Methods and resultsSCZ-associated genes (HTR2A, COMT, and PRODH) were subjected to pan-cancer analysis. COX regression analysis and survival analysis were carried out for differentially expressed genes in multiple cancers, and finally, GBMLGG was derived as the focus for further detailed analysis. The immune scores and immune cell infiltration analyses were performed. All three genes were considerably linked with immune infiltration in GBMLGG, consistent with survival analysis. Based on the immunocyte analysis, it was observed that CD8+ T cells might be critically involved in the survival of GBMLGG. Genomic heterogeneity studies identified correlations of three genes with GBMLGG in tumor mutational burden (TMB) and mutant-allele tumor heterogeneity (MATH). HTR2A and COMT were significantly negatively correlated in TMB. Furthermore, it was found that HTR2A had a significant positive correlation with MATH, whereas PRODH had a significant negative correlation with MATH. Accordingly, a survival prediction model was constructed for GBMLGG using these three genes and clinical data, with better results obtained when evaluated in two separate datasets. Finally, gene expression validation and further immunocyte analysis were carried out in the single-cell RNA sequencing (scRNA-seq) data of glioma.
ConclusionSCZ-associated genes (HTR2A, COMT, and PRODH) were significantly differentially expressed in the carcinogenesis and survival of multiple cancers. The up or downregulation of gene expression varied across cancer types. In the GBMLGG analysis, upregulation of HTR2A and COMT was significantly positively correlated with carcinogenesis, while the opposite was noted for PRODH. Furthermore, a negative correlation was found between the upregulation of HTR2A and COMT and the survival of GBMLGG, and the opposite was also noted for PRODH. As reflected in the immunocyte analysis, abnormal expression of the three genes might be linked with CD8+ T cell infiltration, which might be critically involved in the survival of GBMLGG patients. The expression of HTR2A and COMT may inversely affect the efficacy of immunotherapy through the TMB pathway and further affect the prognosis of patient survival. The expression of HTR2A might positively indicate the degree of tumor heterogeneity through MATH and further affect the survival and prognosis of patients. The negative correlation of PRODH led to the opposite effect. Finally, the constructed survival prediction model demonstrated good predictive value, which was well validated in scRNA-seq analysis.

【背景】精神分裂症（schizophrenia, SCZ）患者的预期寿命缩短可能与多数癌症存在关联，但现有相关研究间存在异质性。本研究通过泛癌分析（pan-cancer analysis）探究了精神分裂症相关基因HTR2A、COMT及PRODH的表达情况，旨在深化对精神分裂症与癌症关联及其遗传层面免疫机制的机制性认知。此外，本研究还构建了针对胶质母细胞瘤与低级别胶质瘤（GBMLGG）的生存预测模型。
【方法与结果】本研究对精神分裂症相关基因HTR2A、COMT及PRODH开展泛癌分析。针对多种癌症中的差异表达基因进行COX回归分析与生存分析，最终选定GBMLGG作为后续深入分析的研究对象。随后进行了免疫评分与免疫细胞浸润分析。生存分析结果显示，这三个基因在GBMLGG中的免疫浸润均存在显著关联。免疫细胞分析表明，CD8+ T细胞可能在GBMLGG患者的生存过程中发挥关键作用。基因组异质性研究则明确了三个基因与GBMLGG的肿瘤突变负荷（tumor mutational burden, TMB）及突变等位基因肿瘤异质性（mutant-allele tumor heterogeneity, MATH）之间的相关性：HTR2A与COMT在TMB水平上呈显著负相关；此外，HTR2A与MATH呈显著正相关，而PRODH与MATH呈显著负相关。基于此，本研究利用这三个基因及临床数据构建了GBMLGG的生存预测模型，在两个独立数据集的验证中均取得了良好的预测效果。最后，通过胶质瘤的单细胞RNA测序（single-cell RNA sequencing, scRNA-seq）数据完成了基因表达验证，并开展了进一步的免疫细胞分析。
【结论】精神分裂症相关基因HTR2A、COMT及PRODH在多种癌症的发生发展与患者生存中均存在显著的差异表达，且基因的上调或下调模式因癌症类型而异。在GBMLGG分析中，HTR2A与COMT的上调与癌症发生呈显著正相关，而PRODH的上调则呈现相反的关联模式。此外，HTR2A与COMT的上调与GBMLGG患者的生存呈负相关，PRODH的上调则呈现相反的关联。免疫细胞分析结果显示，这三个基因的异常表达可能与CD8+ T细胞浸润相关，而后者可能在GBMLGG患者的生存过程中发挥关键作用。HTR2A与COMT的表达可能通过TMB通路反向影响免疫治疗疗效，进而影响患者的生存预后；HTR2A的表达可通过MATH指标正向反映肿瘤异质性程度，进而影响患者的生存与预后，而PRODH的负相关则会产生相反的效应。最终构建的生存预测模型展现出良好的预测价值，且该结果在scRNA-seq分析中得到了有效验证。