Role of tumor mutation burden-related signatures in the prognosis and immune microenvironment of pancreatic ductal adenocarcinoma

Abstract

Background High tumor mutation burden (TMB) has gradually become a sensitive biomarker for predicting the response to immunotherapy in many cancers, including lung, bladder and head and neck cancers. However, whether high TMB predicts the response to immunotherapy and prognosis in pancreatic ductal adenocarcinoma (PDAC) remained obscure. Hence, it is significant to investigate the role of genes related to TMB (TRGs) in PDAC. Methods The transcriptome and mutation data of PDAC was downloaded from The Cancer Genome Atlas-Pancreatic Adenocarcinoma (TCGA). Five independent external datasets of PDAC were chosen to validate parts of our results. qRT-PCR and immunohistochemical staining were also performed to promote the reliability of this study. Results The median overall survival (OS) was significantly increased in TMB_low group compared with the counterpart with higher TMB score after tumor purity adjusted (P = 0.03). 718 differentially expressed TRGs were identified and functionally enriched in some oncogenic pathways. 67 TRGs were associated with OS in PDAC. A prognostic model for the OS was constructed and showed a high predictive accuracy (AUC = 0.849). We also found TMB score was associated with multiple immune components and signatures in tumor microenvironment. In addition, we identified a PDAC subgroup featured with TMBlowMicrosatellite instabilityhigh (MSIhigh) was associated with prolonged OS and a key molecule, ANKRD55, potentially mediating the survival benefits. Conclusion This study analyzed the biological function, prognosis value, implications for mutation landscape and potential influence on immune microenvironment of TRGs in PDAC, which contributed to get aware of the role of TMB in PDAC. Future studies are expected to investigate how these TRGs regulate the initiation, development or repression of PDAC.

Identification of tumour immune microenvironment-related alternative splicing events for the prognostication of pancreatic adenocarcinoma

“…In this study, we mined seven DEASs from the perspective of the TIME and constructed a prognostic signature to evaluate the response to immunotherapy and clinical outcomes of PAAD patients. High-risk group patients with unsatisfying outcomes presented higher mutation patterns and may respond positively to immunotherapy, which is consistent with the conclusion reached by Tang et al [ 50 ]. Unexpectedly, our signature revealed that high-risk PAAD patients have lower infiltration levels of CD8 T cells, regulatory T cells, and activated memory CD4 T cells.…”

Integrated Analysis of Necroptosis-Related Genes for Prognosis, Immune Microenvironment Infiltration, and Drug Sensitivity in Colon Cancer

“…Accumulating evidence suggests that high TMB status is associated with clinical response to immunotherapy in a variety of tumors ( 34 , 35 ). Therefore, we evaluated the distribution of somatic genomic mutations between different NRS-score groups in the TCGA-CORD cohort ( Figures 9A,B ).…”

Construction of a novel signature and prediction of the immune landscape in gastric cancer based on necroptosis-related genes

“…Evidence is growing that high TMB is a feature associated with response to immunotherapy in a variety of tumors, and high TMB levels lead to an increase in tumor neoantigens, which may trigger the immune system to attack the tumor 40 , 41 . Thus, we assessed the correlation of risk score with TMB in the TCGA-GC cohort.…”