Abstract
The aim of any surgical resection for pancreatic ductal adenocarcinoma (PDAC) is to achieve tumor-free margins (R0). R0 margins give rise to better outcomes than do positive margins (R1). Nevertheless, postoperative morbidity after R0 resection remains high and prognostic gene signature predicting recurrence risk of patients in this subgroup is blank. Our study aimed to develop a DNA replication-related gene signature to stratify the R0-treated PDAC patients with various recurrence risks. We conducted Cox regression analysis and the LASSO algorithm on 273 DNA replication-related genes and eventually constructed a 7-gene signature. The predictive capability and clinical feasibility of this risk model were assessed in both training and external validation sets. Pathway enrichment analysis showed that the signature was closely related to cell cycle, DNA replication, and DNA repair. These findings may shed light on the identification of novel biomarkers and therapeutic targets for PDAC.
Highlights
Pancreatic ductal adenocarcinoma (PDAC) accounts for over 90% cases of pancreatic malignancies, and is characterized by an overall 5 years survival rate of less than 9% (Hackeng et al, 2016; Siegel et al, 2019)
positive margin (R1) resection was related to shorter recurrence-free survival (RFS) in the MTAB-6134 dataset (HR = 2.15, 95% CI = 1.53–3.02, P < 0.0001, Figure 1C) and The Cancer Genome Atlas (TCGA) dataset (HR = 2.13, 1.39–3.27, P = 0.0004, Figure 1D)
pancreatic ductal adenocarcinoma (PDAC) patients with tumor-free margin (R0) resection had lower recurrence rates than did patients with R1 resection in the MTAB-6134 dataset (71 vs. 92%, P = 0.0018, Figure 1E) and TCGA dataset (57 vs. 66%, P = 0.2103, Figure 1F). These results suggest that patients with R0 resection had better survival and lower recurrence rates after surgery
Summary
Pancreatic ductal adenocarcinoma (PDAC) accounts for over 90% cases of pancreatic malignancies, and is characterized by an overall 5 years survival rate of less than 9% (Hackeng et al, 2016; Siegel et al, 2019). Complete resection with no microscopic residual disease (R0 resection) is considered the main objective of Abbreviations: AIC, Akaike Information Criterion; AUC, area under the curve; EGFR, epidermal growth factor receptor; K-M, Kaplan-Meier; PARP, Poly ADP-ribose polymerase; PDAC, pancreatic ductal adenocarcinoma; ROC, receiver operating characteristic; R0, tumor-free margin; R1, positive margin; TCGA, the Cancer Genome Atlas. Even if R0 resection is achieved, more than half of patients subsequently experience local recurrence or distant metastases within 2 years of surgery (Kim et al, 2017; Strobel et al, 2017; Ghaneh et al, 2019; Tummers et al, 2019). Effective prediction of recurrence may help to tailor adjuvant chemotherapy and postoperative surveillance in this subgroup of patients
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