■结直肠癌(CRC)是全球第三大流行癌症。积累的数据强调了端粒在CRC癌变和进展中的生物学意义。然而,关于端粒相关基因(TRGs)如何影响CRC预后的研究尚不清楚。因此,本研究的目的是探讨TRGs在CRC预后中的作用.
■我们从公共数据库中回顾性获得CRC患者的表达谱和临床数据。利用最小绝对收缩和选择算子(LASSO)回归分析,我们创建了端粒相关风险模型来预测生存结果,鉴定10个端粒相关差异表达基因(TRDEGs)。基于TRDEGS,我们将癌症基因组图谱(TCGA)中的患者分为低风险和高风险亚群.随后,我们进行了全面分析,包括生存评估,免疫细胞浸润,药物敏感性,并使用卡普兰-迈耶曲线预测分子相互作用,估计,CIBERSORT,OncoPredict,和其他方法。
■该模型对生存显示出出色的预测准确性。根据模型分组的两组参与者之间的生存率存在显着差异(P<0.001),这种差异在外部验证集(GSE39582)中得到进一步证实(P=0.004).此外,与低风险组相比,高风险组表现出明显的晚期肿瘤淋巴结转移(TNM)分期,激活的CD4+T细胞比例较低,效应记忆CD4+T细胞,和记忆B细胞,但M2巨噬细胞和调节性T细胞(Tregs)的比例增加,肿瘤免疫功能障碍和排斥(TIDE)评分升高,对dabrafenib的敏感性降低,拉帕替尼,喜树碱,多西他赛,和端粒酶抑制剂IX,反映签名的区分临床病理特征的能力,免疫环境,和药物功效。最后,我们验证了十个TRDEGs(ACACB,TPX2,SRPX,PPARGC1A,CD36,MMP3,NAT2,MMP10,HIGD1A,和MMP1)通过定量实时聚合酶链反应(qRT-PCR),发现与正常细胞相比,ACACB的表达水平,HIGD1A,NAT2,PPARGC1A,CRC细胞中的TPX2升高,而CD36,SRPX,MMP1、MMP3和MMP10降低。
■总的来说,我们构建了端粒相关生物标志物,能够预测CRC个体的预后和治疗反应,为药物治疗选择和预后预测提供潜在指导。
UNASSIGNED: Colorectal cancer (CRC) is the third-most prevalent cancer globally. The biological significance of telomeres in CRC carcinogenesis and progression is underscored by accumulating data. Nevertheless, not much is known about how
telomere-related genes (TRGs) affect CRC prognosis. Therefore, the aim of this study was to investigate the role of TRGs in CRC prognosis.
UNASSIGNED: We retrospectively obtained the expression profiles and clinical data of CRC patients from public databases. Utilizing least absolute shrinkage and selection operator (LASSO) regression analysis, we created a
telomere-related risk model to predict survival outcomes, identifying ten
telomere-related differentially expressed genes (TRDEGs). Based on TRDEGs, we stratified patients from The Cancer Genome Atlas (TCGA) into low- and high-risk subsets. Subsequently, we conducted comprehensive analyses, including survival assessment, immune cell infiltration, drug sensitivity, and prediction of molecular interactions using Kaplan-Meier curves, ESTIMATE, CIBERSORT, OncoPredict, and other approaches.
UNASSIGNED: The model showed exceptional predictive accuracy for survival. Significant differences in survival were observed between the two groups of participants grouped according to the model (P<0.001), and this difference was further confirmed in the external validation set (GSE39582) (P=0.004). Additionally, compared to the low-risk group, the high-risk group exhibited significantly advanced tumor node metastasis (TNM) stages, lower proportions of activated CD4+ T cells, effector memory CD4+ T cells, and memory B cells, but increased ratios of M2 macrophages and regulatory T cells (Tregs), elevated tumor immune dysfunction and exclusion (TIDE) scores, and diminished sensitivity to dabrafenib, lapatinib, camptothecin, docetaxel, and telomerase inhibitor IX, reflecting the signature\'s capacity to distinguish clinical pathological characteristics, immune environment, and drug efficacy. Finally, we validated the expression of the ten TRDEGs (ACACB, TPX2, SRPX, PPARGC1A, CD36, MMP3, NAT2, MMP10, HIGD1A, and MMP1) through quantitative real-time polymerase chain reaction (qRT-PCR) and found that compared to normal cells, the expression levels of ACACB, HIGD1A, NAT2, PPARGC1A, and TPX2 in CRC cells were elevated, whereas those of CD36, SRPX, MMP1, MMP3, and MMP10 were reduced.
UNASSIGNED: Overall, we constructed a
telomere-related biomarker capable of predicting prognosis and treatment response in CRC individuals, offering potential guidance for drug therapy selection and prognosis prediction.