Development and validation of a hypoxia-stemness-based prognostic signature in pancreatic adenocarcinoma

Abstract

Background: Pancreatic adenocarcinoma (PAAD) is one of the most aggressive and fatal gastrointestinal malignancies with high morbidity and mortality worldwide. Accumulating evidence has revealed the clinical significance of the interaction between the hypoxic microenvironment and cancer stemness in pancreatic cancer progression and therapies. This study aims to identify a hypoxia-stemness index-related gene signature for risk stratification and prognosis prediction in PAAD.Methods: The mRNA expression-based stemness index (mRNAsi) data of PAAD samples from The Cancer Genome Atlas (TCGA) database were calculated based on the one-class logistic regression (OCLR) machine learning algorithm. Univariate Cox regression and LASSO regression analyses were then performed to establish a hypoxia-mRNAsi-related gene signature, and its prognostic performance was verified in both the TCGA-PAAD and GSE62452 corhorts by Kaplan-Meier and receiver operating characteristic (ROC) analyses. Additionally, we further validated the expression levels of signature genes using the TCGA, GTEx and HPA databases as well as qPCR experiments. Moreover, we constructed a prognostic nomogram incorporating the eight-gene signature and traditional clinical factors and analyzed the correlations of the risk score with immune infiltrates and immune checkpoint genes.Results: The mRNAsi values of PAAD samples were significantly higher than those of normal samples (p < 0.001), and PAAD patients with high mRNAsi values exhibited worse overall survival (OS). A novel prognostic risk model was successfully constructed based on the eight-gene signature comprising JMJD6, NDST1, ENO3, LDHA, TES, ANKZF1, CITED, and SIAH2, which could accurately predict the 1-, 3-, and 5-year OS of PAAD patients in both the training and external validation datasets. Additionally, the eight-gene signature could distinguish PAAD samples from normal samples and stratify PAAD patients into low- and high-risk groups with distinct OS. The risk score was closely correlated with immune cell infiltration patterns and immune checkpoint molecules. Moreover, calibration analysis showed the excellent predictive ability of the nomogram incorporating the eight-gene signature and traditional clinical factors.Conclusion: We developed a hypoxia-stemness-related prognostic signature that reliably predicts the OS of PAAD. Our findings may aid in the risk stratification and individual treatment of PAAD patients.

Novel prognostic gene signature for pancreatic ductal adenocarcinoma based on hypoxia

“…To evaluate the prediction accuracy of the prognosis signature, we calculated the C-index for all published hypoxia-related prognostic signatures in PDAC, whereby a C-index greater than 0.7 is considered indicative of an accurate model. Additionally, we compared the predictive performance of our signature with cell death signatures (autophagy, cuproptosis, ferroptosis, and pyroptosis signatures) [ 60 – 66 ]. The results showed that the C-index of our signature (0.7286131 in training sets, 0.6163404 in validation sets) surpassed that of other models in both the training and validation sets (Fig.…”

Cuprotosis Programmed-Cell-Death-Related lncRNA Signature Predicts Prognosis and Immune Landscape in PAAD Patients

“…These genes included CD200R1, CD200, TNFRSF4, ICOSLG, ADORA2A, CD160, BTNL2, TNSF14, PDCD1, CD48, CD40LG, TNFRSF25, LAG3, TNFRSF8, CD27, LAIR1, CTLA4, and BTLA ( Figure 10 C). In PAAD, an increased expression of CD44, a marker for cancer stem cells, was closely linked to tumor recurrence and a poor prognosis [ 39 ]. The above-mentioned discrepancies in the expression of invading immune cells between the high- and low-risk groups may be explained by the fact that TNFSF9 was strongly expressed in pancreatic cancer tissues and linked with the M1 polarization of macrophages [ 40 ].…”

Profiling of a novel circadian clock-related prognostic signature and its role in immune function and response to molecular targeted therapy in pancreatic cancer

“…FBXL17, FBXL8, CDK1, CSNK1D, and PSPC1 have not been well studied in pancreatic ductal cancer. However, several of them have been implicated in pancreatic cancer, with a relatively high expression and a poor survival [30][31][32][33]. These suggest that the 13 genes in this prognostic signature are worth further investigation for their potential as novel therapeutic targets.…”