A prognostic binary classifier comprised of five critical mRNAs stratified pancreatic cancer patients following resection.

Background: Pancreatic cancer is characterized by an extremely poor prognosis, even following potentially curative resection. Classical prognostic markers such as histopathological or clinical parameters have limited predictive power. The present study aimed to establish a prognostic model combining mRNA expression data with histopathological and clinical data to better predict survival and stratify pancreatic cancer patients following resection. We pioneered three models in one study and systematically evaluated the clinical benefits of all three models.

Methods: To identify differentially expressed genes in pancreatic cancer, mRNA data from normal (GTEx database) and pancreatic cancer (TCGA database) tissues were used. Survival analysis was carried out to identify prognosis-relevant genes from the identified differentially expressed genes and LASSO regression was used to filter out hub genes. The risk score of several hub genes was calculated according to gene expression and coefficients. Validation was carried out using an independent set of GEO microarray data. Multivariate COX regression was used for identifying independent clinical and pathological risk factors related to patient's survival in the TCGA database and a prognostic model combining mRNA expression data with histopathological and clinical data was established. Another prognostic model using clinicopathological factors from the SEER database was conceived based on multivariate COX regression. NRI (net reclassification improvement) and IDI (integrated discrimination index) were used to compare the predictive capabilities of the different models.

Results: We identified 1589 differentially expressed genes (DEGs) through the comparison of normal and pancreatic cancer tissues, of whom 317 were associated with prognosis(p < 0.05). LASSO regression identified five hub genes, MYEOV, ANXA2P2, MET, CEP55, and KRT7, that were used for the five-mRNA-classifier prognostic model. The classifier could stratify patients into a short and long survival group: 5-year overall survival in the training set (TCGA, 6 % vs 52 %, p < 0.001), test set (TCGA, 18 % vs 55 %,p < 0.01) and external validation set (GEO, 0 % vs 25 %, p < 0.05). Sensitivity analysis showed that the mRNA model (model 1) was better than the clinicopathological no-mRNA model (model 2) in predicting 5-year survival in the TCGA database (AUC: 0.877 vs 0.718, z = 3.165, p < 0.01) and better than the multi-factor prognostic model (model 3) from the SEER database (AUC: 0.754, z = 2.637, p < 0.01). On predictive performance, model 1 improved model 2 (NRI = 0.084, z = 1.288, p = 0.198; IDI = 0.055, z = 1.041,p = 0.298) and model 3 (NRI = 0.167,z = 1.961,p = 0.05; IDI = 0.086, z = 1.427, p = 0.154).

Conclusion: The five-mRNA-classifier is a reliable and feasible instrument to predict the prognosis of pancreatic cancer patients following resection. It might help in patiens counseling and assist clinicians in providing individualized treatment for patients in different risk groups.