DataSheet_3_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恶性肿瘤存在关联，但现有相关研究的结论存在异质性。本研究通过泛癌分析（pan-cancer analysis）探究了SCZ相关基因（HTR2A、COMT及PRODH）的表达特征，旨在从遗传层面深化对SCZ与癌症关联机制及其免疫机制的理解。此外，本研究还构建了针对胶质母细胞瘤与低级别胶质瘤（glioblastoma and low-grade glioma, GBMLGG）的生存预测模型。

【方法与结果】首先对SCZ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，最终筛选出GBMLGG作为后续深入分析的核心对象。随后开展免疫评分与免疫细胞浸润分析，结果显示GBMLGG中上述三个基因的表达均与免疫浸润显著相关，这与生存分析结果一致。免疫细胞分析提示，CD8+ T细胞可能在GBMLGG的生存进程中发挥关键作用。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）的关联：HTR2A与COMT的表达在TMB层面呈显著负相关；HTR2A的表达与MATH呈显著正相关，而PRODH的表达与MATH呈显著负相关。基于上述结果，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，在两个独立数据集上的验证均取得了良好效果。最后，本研究在胶质瘤的单细胞RNA测序（single-cell RNA sequencing, scRNA-seq）数据中完成了基因表达验证与进一步的免疫细胞分析。

【结论】SCZ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的分析中，HTR2A与COMT的上调与肿瘤发生呈显著正相关，而PRODH的上调则呈现相反趋势；同时，HTR2A与COMT的上调与GBMLGG患者的生存呈负相关，PRODH的上调则呈现相反关联。免疫细胞分析结果显示，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患者的生存进程中发挥关键作用。HTR2A与COMT的表达可通过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的负相关关联则会产生相反的效应。本研究构建的生存预测模型具备良好的预测价值，并在scRNA-seq分析中得到了有效验证。