背景:蛋白酶体26S亚基,ATP酶基因(PSMC)家族成员在调节蛋白质降解中起关键作用,并且对肿瘤的发展至关重要。然而,关于PSMC基因家族成员在肺癌中的整合功能和预后意义知之甚少。方法:首先,我们从癌症基因组图谱(TCGA)数据集评估了6个PSMC家族成员在泛癌症中的表达和预后特征.因此,通过关注PSMC基因与预后之间的关系,基因组,和肺腺癌(LUAD)的肿瘤微环境特征,使用共识聚类和多种机器学习算法建立了基于PSMC的预后签名,包括最小绝对收缩和选择算子(LASSO)Cox回归,CoxBoost,TCGA和GSE72094中的生存随机森林分析。然后,我们在来自GEO的三个独立队列中验证了它,并估计了风险评分和临床特征之间的相关性:基因组特征(改变,肿瘤突变负荷,和拷贝数变体),免疫概况(免疫评分,潮流得分,肿瘤浸润的免疫细胞,和免疫检查点),对化疗的敏感性(GDSC,GSE42127和GSE14814),和免疫疗法(IMvenerg210、GSE63557和免疫表型)。21名LUAD患者被纳入我们的当地队列,并提交肿瘤样本评估风险基因和PD-L1表达。结果:几乎所有6个PSMC基因在全癌肿瘤组织中都过表达;然而,仅在LUAD,它们都与总生存期显著相关.值得注意的是,他们都与增加的TMB有积极的联系,潮流得分,免疫检查点(CD276和PVR)的表达,和更多的M1巨噬细胞,但降低B细胞丰度。基于来自PSMC基因差异表达簇的五个hub基因,建立了基于PSMC的预后特征。并根据中位风险评分将LUAD患者分为高危组和低危组.在训练队列中预测1年、3年和5年生存率的曲线下面积(AUC)值均>.71,在GSE72094、GSE31210和GSE13213数据集中,预测准确性也是稳健和稳定的。风险评分与肿瘤进展显著相关,淋巴结,和肿瘤疾病分期是LUAD的独立危险因素。此外,风险评分与PSMC基因具有相似的基因组和免疫特征,高危肿瘤表现出显著的基因组和染色体不稳定性,TIDE评分较高但免疫评分较低,B和CD8+T细胞丰度降低。最后,研究表明,高危患者对免疫治疗的敏感性较低,但对铂类化疗产生反应的可能性较高.来自局部队列的LUAD样品支持肿瘤和正常组织之间这五个hub基因的表达水平的差异以及风险评分与PD-L1表达之间的相关性。结论:总体而言,我们的结果提供了对LUAD中PSMC基因的深入了解,尤其是可以预测治疗反应的预后效果和相关免疫谱。
Background: Proteasome 26S subunit, ATPase gene (
PSMC) family members play a critical role in regulating protein degradation and are essential for tumor development. However, little is known about the integrative function and prognostic significance of the
PSMC gene family members in lung cancer. Methods: First, we assessed the expression and prognostic features of six
PSMC family members in pan-cancer from The Cancer Genome Atlas (TCGA) dataset. Hence, by focusing on the relationship between PSMC genes and the prognostic, genomic, and tumor microenvironment features in lung adenocarcinoma (LUAD), a
PSMC-based prognostic signature was established using consensus clustering and multiple machine learning algorithms, including the least absolute shrinkage and selection operator (LASSO) Cox regression, CoxBoost, and survival random forest analysis in TCGA and GSE72094. We then validated it in three independent cohorts from GEO and estimated the correlation between risk score and clinical features: genomic features (alterations, tumor mutation burden, and copy number variants), immune profiles (immune score, TIDE score, tumor-infiltrated immune cells, and immune checkpoints), sensitivity to chemotherapy (GDSC, GSE42127, and GSE14814), and immunotherapy (IMvigor210, GSE63557, and immunophenoscore). Twenty-one patients with LUAD were included in our local cohort, and tumor samples were submitted for evaluation of risk gene and PD-L1 expression. Results: Nearly all six PSMC genes were overexpressed in pan-cancer tumor tissues; however, in LUAD alone, they were all significantly correlated with overall survival. Notably, they all shared a positive association with increased TMB, TIDE score, expression of immune checkpoints (CD276 and PVR), and more M1 macrophages but decreased B-cell abundance. A PSMC-based prognostic signature was established based on five hub genes derived from the differential expression clusters of PSMC genes, and it was used to dichotomize LUAD patients into high- and low-risk groups according to the median risk score. The area under the curve (AUC) values for predicting survival at 1, 3, and 5 years in the training cohorts were all >.71, and the predictive accuracy was also robust and stable in the GSE72094, GSE31210, and GSE13213 datasets. The risk score was significantly correlated with advanced tumor, lymph node, and neoplasm disease stages as an independent risk factor for LUAD. Furthermore, the risk score shared a similar genomic and immune feature as
PSMC genes, and high-risk tumors exhibited significant genomic and chromosomal instability, a higher TIDE score but lower immune score, and a decreased abundance of B and CD8+ T cells. Finally, high-risk patients were suggested to be less sensitive to immunotherapy but had a higher possibility of responding to platinum-based chemotherapy. The LUAD samples from the local cohort supported the difference in the expression levels of these five hub genes between tumor and normal tissues and the correlation between the risk score and PD-L1 expression. Conclusion: Overall, our results provide deep insight into PSMC genes in LUAD, especially the prognostic effect and related immune profile that may predict therapeutic responses.