The DNA mismatch repair landscape in pancreatic adenocarcinoma: a novel prognostic signature with implications for immune microenvironment and chemotherapy response
Year: 2026
Type: article
Abstract: Background: 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. Methods: 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. Results: 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. Conclusions: 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.
Source: Translational Cancer Research
Language: English
Subfield: Oncology
Field: Medicine
Domain: Health Sciences
Open Access status: diamond
OpenAlex ID: W7224116806