The DNA mismatch repair landscape in pancreatic adenocarcinoma: a novel prognostic signature with implications for immune microenvironment and chemotherapy response.
4 affiliations
- 1Department of Pharmacy, Gaoxin Hospital, Affiliated to West China Second School of Medicine, Sichuan University, Chengdu, China.
- 2Department of Pharmacy, The Affiliated Hospital of Southwest Medical University, Luzhou, China.
- 3School of Pharmacy, Southwest Medical University, Luzhou, China.
- 4Department of Pharmacy, The Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University, Luzhou, China.
Abstract
Pancreatic adenocarcinoma (PAAD) is a lethal malignancy with a notoriously poor prognosis. While the DNA mismatch repair (MMR) system is crucial for genomic integrity and its deficiency influences immunotherapy response in some cancers, its comprehensive prognostic value and association with tumor microenvironment (TME) in PAAD remain underexplored. We aimed to construct and validate an MMR-related prognostic signature and explore its associations with TME and chemotherapy sensitivity in PAAD. Both the RNA sequencing data and clinical data for PAAD were acquired through The Cancer Genome Atlas (TCGA) database. Prognosis-related MMR genes were screened, and a risk-scoring model was constructed by least absolute shrinkage and selection operator (LASSO) regression and multivariate Cox regression analyses, validated using Gene Expression Omnibus (GEO) datasets (GSE78229 and GSE57495). The predictive performance was assessed using Kaplan-Meier (K-M) survival and Receiver operating characteristic (ROC) curve analyses. The model's association with genetic alterations, immune cell infiltration (analyzed with CIBERSORT, QUANTISEQ, and EPIC algorithms), immunotherapy response [Tumor Immune Dysfunction and Exclusion (TIDE), tumor mutational burden (TMB), and immunophenoscore (IPS) scores], and chemotherapy sensitivity was systematically investigated. Six MMR genes (HDAC10, MSH2, MSH4, PCNA, PRKCG, and RPA1) were established. Patients were stratified into high- and low-risk groups with significantly distinct overall survival (OS) (P<0.001). The risk score demonstrated robust predictive accuracy for 5-year survival [area under the curve (AUC) =0.857] and was an independent prognostic factor. The low-risk group exhibited an immunologically active TME, with increased infiltration of CD8+ T cells and naive B cells. In contrast, the high-risk group had a significantly higher TME score, whereas TMB and TIDE scores did not differ significantly between the two groups. Drug sensitivity analysis revealed that the high-risk group was more sensitive to gemcitabine and paclitaxel. We developed and validated a novel six-MMR-gene signature that effectively predicts prognosis, reflects the immune contexture, and suggests differential chemotherapy sensitivity in PAAD. This signature provides a potential multi-dimensional biomarker for risk stratification and personalized treatment planning.
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BibTeX
@article{tang2026mismatch,
title = {{The DNA mismatch repair landscape in pancreatic adenocarcinoma: a novel prognostic signature with implications for immune microenvironment and chemotherapy response.}},
author = {Hui Tang and Xuping Yang and Xiao Duan and Jia Feng and Changjing Xu and Yilan Huang and Longyang Jiang},
journal = {Translational cancer research},
year = {2026},
month = may,
doi = {10.21037/tcr-2026-1-0007},
url = {https://europepmc.org/article/MED/42997921},
note = {CC BY-NC-ND},
}
RIS
TY - JOUR
TI - The DNA mismatch repair landscape in pancreatic adenocarcinoma: a novel prognostic signature with implications for immune microenvironment and chemotherapy response.
AU - Hui Tang
AU - Xuping Yang
AU - Xiao Duan
AU - Jia Feng
AU - Changjing Xu
AU - Yilan Huang
AU - Longyang Jiang
PY - 2026
DA - 2026/05/18
JO - Translational cancer research
DO - 10.21037/tcr-2026-1-0007
UR - https://europepmc.org/article/MED/42997921
AB - Pancreatic adenocarcinoma (PAAD) is a lethal malignancy with a notoriously poor prognosis. While the DNA mismatch repair (MMR) system is crucial for genomic integrity and its deficiency influences immunotherapy response in some cancers, its comprehensive prognostic value and association with tumor microenvironment (TME) in PAAD remain underexplored. We aimed to construct and validate an MMR-related prognostic signature and explore its associations with TME and chemotherapy sensitivity in PAAD. Both the RNA sequencing data and clinical data for PAAD were acquired through The Cancer Genome Atlas (TCGA) database. Prognosis-related MMR genes were screened, and a risk-scoring model was constructed by least absolute shrinkage and selection operator (LASSO) regression and multivariate Cox regression analyses, validated using Gene Expression Omnibus (GEO) datasets (GSE78229 and GSE57495). The predictive performance was assessed using Kaplan-Meier (K-M) survival and Receiver operating characteristic (ROC) curve analyses. The model's association with genetic alterations, immune cell infiltration (analyzed with CIBERSORT, QUANTISEQ, and EPIC algorithms), immunotherapy response [Tumor Immune Dysfunction and Exclusion (TIDE), tumor mutational burden (TMB), and immunophenoscore (IPS) scores], and chemotherapy sensitivity was systematically investigated. Six MMR genes (HDAC10, MSH2, MSH4, PCNA, PRKCG, and RPA1) were established. Patients were stratified into high- and low-risk groups with significantly distinct overall survival (OS) (P<0.001). The risk score demonstrated robust predictive accuracy for 5-year survival [area under the curve (AUC) =0.857] and was an independent prognostic factor. The low-risk group exhibited an immunologically active TME, with increased infiltration of CD8+ T cells and naive B cells. In contrast, the high-risk group had a significantly higher TME score, whereas TMB and TIDE scores did not differ significantly between the two groups. Drug sensitivity analysis revealed that the high-risk group was more sensitive to gemcitabine and paclitaxel. We developed and validated a novel six-MMR-gene signature that effectively predicts prognosis, reflects the immune contexture, and suggests differential chemotherapy sensitivity in PAAD. This signature provides a potential multi-dimensional biomarker for risk stratification and personalized treatment planning.
SN - 2218-676X
SN - 2219-6803
ER -