A qualitative transcriptional prognostic signature for patients with stage I-II pancreatic ductal adenocarcinoma

Abstract Accurately prognostic evaluation of patients with stage I-II pancreatic ductal adenocarcinoma (PDAC) is of importance to treatment decision and patient management. Most previously reported prognostic signatures were based on risk scores summarized from quantitative expression measurements of signature genes, which are susceptible to experimental batch effects and impractical for clinical applications. Based on the within-sample relative expression orderings (REOs) of genes, we developed a robust qualitative transcriptional prognostic signature, consisting of 64 gene pairs (64-GPS), to predict the overall survival (OS) of 161 stage I-II PDAC patients in the training dataset who were treated with surgery only. Samples were classified into the high-risk group when at least 25 of 64 gene pairs suggested it was at high risk. The signature was successfully validated in 324 samples from six independent datasets produced by different laboratories. All samples in the low-risk group had significantly better OS than samples in the high-risk group. Multivariate Cox regression analyses showed that the 64-GPS remained significantly associated with the OS of patients after adjusting available clinical factors. Transcriptomic analysis of the two prognostic subgroups showed that the differential expression signals were highly reproducible in all datasets, whereas the differences between samples grouped by the TNM staging system were weak and irreproducible. The epigenomic analysis showed that the epigenetic alternations may cause consistently transcriptional changes between the two different prognostic groups. The genomic analysis revealed that mutation‑induced disturbances in several key genes, such as LRMDA, MAPK10 and CREBBP, might lead to poor prognosis for PDAC patients. Conclusively, the 64-GPS can robustly predict the prognosis of patients with stage I-II PDAC, which provides theoretical basis for clinical individualized treatment.