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. 2021 Mar 4:9:619549.
doi: 10.3389/fcell.2021.619549. eCollection 2021.

A Novel DNA Replication-Related Signature Predicting Recurrence After R0 Resection of Pancreatic Ductal Adenocarcinoma: Prognostic Value and Clinical Implications

Zengyu Feng  1   2   3 , Kexian Li  1   2 , Jianyao Lou  3 , Mindi Ma  4 , Yulian Wu  3 , Chenghong Peng  1   2
Affiliations

A Novel DNA Replication-Related Signature Predicting Recurrence After R0 Resection of Pancreatic Ductal Adenocarcinoma: Prognostic Value and Clinical Implications

Zengyu Feng et al. Front Cell Dev Biol. .

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.

Keywords: DNA replication; R0 resection; pancreatic ductal adenocarcinoma; prognostic signature; recurrence; risk score.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

FIGURE 1
FIGURE 1
Survival difference between R0 and R1 treated patients. (A,B) K-M curves estimate OS difference between R0 and R1 margin. (C,D) K-M curves of RFS between patients with R0 and R1 resection. (E,F) Relationship of resection margin status and recurrence rate.
FIGURE 2
FIGURE 2
Development of the DNA replication-related signature. (A) Cross-validation for tuning parameter (lambda) screening in the LASSO regression model. (B) LASSO coefficient profiles of 20 prognostic DNA replication-related genes. (C) Forest plot of the seven DNA replication-related genes. (D) Survival cure for EREG. (E) Survival cure for KCTD13. (F) Survival cure for MCM3AP. (G) Survival cure for MCM7. (H) Survival cure for POLG2. (I) Survival cure for TERF2. (J) Survival cure for TP73. ∗p < 0.05; ∗∗p < 0.01; ∗∗∗p < 0.001.
FIGURE 3
FIGURE 3
Prognostic performance of risk signature in MTAB-6134 cohort. (A) From top to bottom are the survival status distribution, risk score distribution and heat map analysis of seven genes. (B) RFS difference between low- and high-risk groups. (C) ROC analysis of the risk signature. (D) Calibration curves for risk score. (E) Univariate and (F) multivariate Cox regression analyses of clinical pathologic features and gene signature for RFS. (G) Distribution of risk scores in different histological grade.
FIGURE 4
FIGURE 4
Prognostic performance of risk signature in TCGA cohort. (A) From top to bottom are the patients’ survival overview, risk score, and heat map of seven prognostic genes expression. (B) K–M curves evaluating the RFS between low- and high-risk groups. (C) ROC curve analysis of risk score in TCGA cohort. (D) Calibration curves for risk score. (E) Univariate and (F) multivariate Cox regression analyses of parameters for RFS. (G) Distribution of risk scores with respect to grade.
FIGURE 5
FIGURE 5
Prognostic validation in a local cohort. (A) K-M curve of RFS in Ruijin cohort. (B) ROC curve of the signature in predicting 1 year RFS in Ruijin cohort.
FIGURE 6
FIGURE 6
Comprehensive analysis of EREG expression in PDAC. (A,B) Expression of EREG in PDAC patients stratified by histological grade in MTAB-6134 and TCGA cohorts. (C) Expression of EREG in tumor tissues and normal tissues. (D) Expression of EREG in pancreatic cell lines based on the RNA-sequencing data downloaded from GSE138437 dataset. (E) Survival curve for EREG in TCGA cohort. *p < 0.05; **p < 0.01; ***p < 0.001.
FIGURE 7
FIGURE 7
Nomogram construction. (A) Nomogram integrating risk score, grade, T stage, and N stage for RFS prediction. (B) K–M survival curve of nomogram in MTAB-6134 cohort. (C) Time-dependent AUC curves of prognostic indicators in MTAB-6134 cohort.
FIGURE 8
FIGURE 8
Functional annotation and pathway enrichment. (A,B) Enriched pathways of the genes positively correlated with risk score in MTAB-6134 cohort and TCGA cohort.
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