Research Paper Volume 15, Issue 1 pp 119—133
Profiling of a novel circadian clock-related prognostic signature and its role in immune function and response to molecular targeted therapy in pancreatic cancer
- 1 Division of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
- 2 First School of Clinic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
Received: October 11, 2022 Accepted: December 20, 2022 Published: January 9, 2023
https://doi.org/10.18632/aging.204462How to Cite
Copyright: © 2023 Jin et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Abstract
Background: Pancreatic ductal adenocarcinoma (PADA) represents a devastating type of pancreatic cancer with high mortality. Defining a prognostic gene signature that can stratify patients with different risk will benefit cancer treatment strategies.
Methods: Gene expression profiles of PADA patients were acquired from the Cancer Genome Atlas and Gene Expression Omnibus, including GSE62452 and GSE28735. Differential expression analysis was carried out using the package edgeR in R. Intro-tumor immune infiltrates were quantified by six different computational algorithms XCELL, TIMER, QUANTISEQ, MCPCOUNTER, EPIC, and CIBERSORT. Biological processes were investigated based on R package “clusterProfiler”.
Results: 13 genes (ARNTL2, BHLHE40, FBXL17, FBXL8, PPP1CB, RBM4B, ADRB1, CCAR2, CDK1, CSNK1D, KLF10, PSPC1, SIAH2) were eligible for the development of a prognostic gene signature. Performance of the prognostic gene signature was assessed in the discovery set (n = 210), validation set (n = 52), and two external data set (GSE62452, n = 65, and GSE28735, n = 84). Area under the curve (AUC) for predicting 3-year overall survival was 0.727, 0.732, 0.700, and 0.658 in the training set, the validation set, and the two test sets, respectively. KM curve revealed that the low-risk group had an improved prognosis than the high-risk group in all four datasets. PCA analysis demonstrated that the low-risk group was apparently separated from the high-risk group. CD8 T cell and B cell were significantly reduced in the high-risk group than in the low-risk group, while neutrophils were significantly augmented in the high-risk group than in the low-risk group. BMS-536924, Foretinib, Linsitinib, and Sabutoclax were more sensitive in the low-risk group, whereas Erlotinib was more effective in the high-risk group.
Conclusions: We successfully established and verified a novel circadian clock-related gene signature, which could stratify patients with different risk and be reflective of the therapeutic effect of molecular targeted therapy. Our findings could incorporate the pharmacological modulation of circadian clock into future therapeutic strategies.