Construction and evaluation of an aging-associated genes-based model for pancreatic adenocarcinoma prognosis and therapies

Objectives: Pancreatic adenocarcinoma (PAAD) is a highly malignant tumor. Despite extensive research, the precise role of aging-related genes in the initiation, microenvironment regulation, and progression of PAAD remains unclear. Methods: Patients with PAAD were selected from the International Cancer Genome Consortium (ICGC), and The Cancer Genome Atlas (TCGA) cohorts and the cell senescence-associated genes were obtained from CellAge. ConsensusClusterPlus was utilized for cluster identification. The least absolute shrinkage and selection operator (LASSO) Cox regression analysis was performed to construct a prognosis prediction model. Results: We identified three clusters (C1, C2, and C3) based on aging-associated gene profiles. The C1 cluster had a shorter overall survival time, advanced clinical grades, lower immune ESTIMATE score, and tumor immune dysfunction and exclusion (TIDE) score than the C3 subgroup. Moreover, signaling pathways for cell cycle activation were enriched in the C1 cluster. We also identified eight hub genes and constructed a risk model. The high cellular senescence-related signature (CSRS) score subtype exhibited poor prognosis, advanced clinical grades, M2 macrophage infiltration, higher immune checkpoint gene expression, and lower immunotherapeutic benefits. Conclusion: Our risk score model shows high prediction accuracy and survival prediction ability in individual clinical prognosis and pre-immunotherapy evaluation.