Transcriptomic correlates of cell cycle checkpoints with distinct prognosis, molecular characteristics, immunological regulation, and therapeutic response in colorectal adenocarcinoma

• DOI: 10.3389/fimmu.2023.1291859
• Publication Date: 2023-12-09T19:08:53Z
• Authors: Heng Wang; Wei Wang; Zhen Wang; Xu Li
• Keywords: Lasso; Gene signature

Backgrounds Colorectal adenocarcinoma (COAD), accounting for the most common subtype of colorectal cancer (CRC), is a kind malignant digestive tumor. Some cell cycle checkpoints (CCCs) have been found to contribute CRC progression, whereas functional roles lot CCCs, especially integrated role checkpoint mechanism in cycle, remain unclear. Materials and methods The Genomic Data Commons (GDC) Cancer Genome Atlas (TCGA) COAD cohort was retrieved as training dataset, GSE24551 GSE29623 were downloaded from Gene Expression Omnibus (GEO) validation datasets. A total 209 CCC-related genes derived Ontology Consortium subsequently enrolled univariate, multivariate, least absolute shrinkage selection operator (LASSO) Cox regression analyses, finally defining CCC signature. Cell proliferation Transwell assay analyses utilized evaluate signature-related CCCs. underlying signature, molecular characteristics, immune-related features, therapeutic response estimated. Genomics Drug Sensitivity (GDSC) database employed evaluation chemotherapeutic responses. Results aberrant gene expression CCCs greatly contributed development progression. Univariate analysis identified 27 significantly affecting overall survival (OS) patients; subsequently, LASSO determined novel Noticeably, CDK5RAP2 , MAD1L1 NBN RGCC ZNF207 first be correlated with prognosis COAD, it proven that all them invasion HCT116 SW480 cells. In TCGA cohort, signature robustly stratified patients into high low score groups (median OS: 57.24 months vs. unreached, p < 0.0001), simultaneously, good AUC values OS prediction at 1, 2, 3 years 0.74, 0.78, 0.77. Furthermore, prognostic capacity verified datasets, independent clinical features. Moreover, higher always indicated worse OS, regardless histological subtypes, or subgroups. Intriguingly, enrichment confirmed markedly associated extracellular, matrix immune (chemokine)-related signaling, cycle-related metabolisms. Impressively, positively majority chemokines, receptors, immunostimulators, anticancer immunity, indicating relatively immune-promoting microenvironment. addition, GSE173839, GSE25066, GSE41998, GSE194040 dataset suggested durvalumab olaparib paclitaxel, taxane-anthracycline chemotherapy, neoadjuvant cyclophosphamide/doxorubicin ixabepilone immunotherapeutic strategies might suitable score. Eventually, GDSC showed lower scores likely more sensitive 5-fluorouracil, bosutinib, gemcitabine, gefitinib, methotrexate, mitomycin C, temozolomide, while seemed level sensitivity bortezomib elesclomol. Conclusion exhibited ability patients, highly responses, which would promote management precision medicine COAD.