Abstract

BackgroundGene mutations play critical roles in tumorigenesis and cancer development. Our study aimed to screen survival-related mutations and explore a novel gene signature to predict the overall survival in pancreatic cancer.MethodsSomatic mutation data from three cohorts were used to identify the common survival-related gene mutation with Kaplan-Meier curves. RNA-sequencing data were used to explore the signature for survival prediction. First, Weighted Gene Co-expression Network Analysis was conducted to identify candidate genes. Then, the ICGC-PACA-CA cohort was applied as the training set and the TCGA-PAAD cohort was used as the external validation set. A TP53-associated signature calculating the risk score of every patient was developed with univariate Cox, least absolute shrinkage and selection operator, and stepwise regression analysis. Kaplan-Meier and receiver operating characteristic curves were plotted to verify the accuracy. The independence of the signature was confirmed by the multivariate Cox regression analysis. Finally, a prognostic nomogram including 359 patients was constructed based on the combined expression data and the risk scores.ResultsTP53 mutation was screened to be the robust and survival-related mutation type, and was associated with immune cell infiltration. Two thousand, four hundred fifty-five genes included in the six modules generated in the WGCNA were screened as candidate survival related TP53-associated genes. A seven-gene signature was constructed: Risk score = (0.1254 × ERRFI1) - (0.1365 × IL6R) - (0.4400 × PPP1R10) - (0.3397 × PTOV1-AS2) + (0.1544 × SCEL) - (0.4412 × SSX2IP) – (0.2231 × TXNL4A). Area Under Curves of 1-, 3-, and 5-year ROC curves were 0.731, 0.808, and 0.873 in the training set and 0.703, 0.677, and 0.737 in the validation set. A prognostic nomogram including 359 patients was constructed and well-calibrated, with the Area Under Curves of 1-, 3-, and 5-year ROC curves as 0.713, 0.753, and 0.823.ConclusionsThe TP53-associated signature exhibited good prognostic efficacy in predicting the overall survival of PC patients.

Highlights

  • Pancreatic cancer (PC) has been the 11th most common cancer in 2012

  • The RNA-sequencing data of the International Cancer Genome Consortium (ICGC)-PACA-CA and the The Cancer Genome Atlas (TCGA)-PAAD cohorts were used to explore and validate the multi-gene signature to predict the overall survival in patients with pancreatic cancer

  • In order to explore whether these mutations were associated with the overall survival robustly, Kaplan-Meier (KM) curves comparing the mutated group with the wild group were performed in the three cohorts separately

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Summary

Introduction

Pancreatic cancer (PC) has been the 11th most common cancer in 2012. Both the incidence and mortality rates of PC have been increasing in developed countries. As the malignancy with the highest mortality, the survival rate of PC has not been increased despite years of investigation [3]. The primary treatment approach is still surgery, though only 20% of patients will survive over 5 years after pancreatectomy [4]. The diagnosis of pancreatic cancer has been generally difficult because it depended on the clinical symptoms, which were not indicative during onset and gradual progression over years. The detection of pancreatic cancer at early and resectable stage has been proved to have beneficial effects on long-term survival. Gene mutations play critical roles in tumorigenesis and cancer development. Our study aimed to screen survival-related mutations and explore a novel gene signature to predict the overall survival in pancreatic cancer

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