Abstract
BackgroundMolecular markers play an important role in predicting clinical outcomes in pancreatic adenocarcinoma (PAAD) patients. Analysis of the ferroptosis-related genes may provide novel potential targets for the prognosis and treatment of PAAD.MethodsRNA-sequence and clinical data of PAAD was downloaded from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) public databases. The PAAD samples were clustered by a non-negative matrix factorization (NMF) algorithm. The differentially expressed genes (DEGs) between different subtypes were used by “limma_3.42.2” package. The R software package clusterProfiler was used for functional enrichment analysis. Then, a multivariate Cox proportional and LASSO regression were used to develop a ferroptosis-related gene signature for pancreatic adenocarcinoma. A nomogram and corrected curves were constructed. Finally, the expression and function of these signature genes were explored by qRT-PCR, immunohistochemistry (IHC) and proliferation, migration and invasion assays.ResultsThe 173 samples were divided into 3 categories (C1, C2, and C3) and a 3-gene signature model (ALOX5, ALOX12, and CISD1) was constructed. The prognostic model showed good independent prognostic ability in PAAD. In the GSE62452 external validation set, the molecular model also showed good risk prediction. KM-curve analysis showed that there were significant differences between the high and low-risk groups, samples with a high-risk score had a worse prognosis. The predictive efficiency of the 3-gene signature-based nomogram was significantly better than that of traditional clinical features. For comparison with other models, that our model, with a reasonable number of genes, yields a more effective result. The results obtained with qPCR and IHC assays showed that ALOX5 was highly expressed, whether ALOX12 and CISD1 were expressed at low levels in tissue samples. Finally, function assays results suggested that ALOX5 may be an oncogene and ALOX12 and CISD1 may be tumor suppressor genes.ConclusionsWe present a novel prognostic molecular model for PAAD based on ferroptosis-related genes, which serves as a potentially effective tool for prognostic differentiation in pancreatic cancer patients.
Highlights
Molecular markers play an important role in predicting clinical outcomes in pancreatic adenocarcinoma (PAAD) patients
We identified ferroptosis-associated genes and constructed molecular subtypes of PAAD based on The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases
58 ferroptosisrelated genes with gene expression data were matched with the TCGA-PAAD data set, and PAAD samples were clustered by non-negative matrix factorization (NMF)
Summary
Molecular markers play an important role in predicting clinical outcomes in pancreatic adenocarcinoma (PAAD) patients. Pancreatic cancer has a low 5-year survival rate and is one of the cancers that have high mortality [1]. Adenocarcinoma is the most common type of pancreatic cancer and accounts for > 90% of the diagnosed pancreatic cancer cases. Despite advances in the treatment of pancreatic adenocarcinoma (PAAD), the 5-year survival rate remains only 9% [4]. There is an urgent need to identify the prognostic biomarkers of PAAD. This would aid clinicians to predict the clinical outcomes promptly and accurately as well as initiate a protocol for a personalized treatment regimen
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