MiRNA-Based Signature Associated With Tumor Mutational Burden in Colon Adenocarcinoma.

Weijie Xue,Weijie Xue,Zhaojian Niu,Yuwei Xie,Yuwei Xie,Chunyang Guan,Yixiu Wang,Chuqing Wei,Chengzhan Zhu,Zhiqi Gong,Chunyang Guan,Zhaojian Niu,Zhiqi Gong,Chenyu Yang

doi:10.3389/fonc.2021.634841

Abstract

Colon adenocarcinoma (COAD) is one of the most common malignant tumors. Tumor mutation burden (TMB) has become an independent biomarker for predicting the response to immune checkpoint inhibitors (ICIs). miRNAs play an important role in cancer-related immune regulation. However, the relationship between miRNA expression and TMB in COAD remains unclear. Therefore, the transcriptome profiling data, clinical data, mutation annotation data, and miRNA expression profiles for cases of COAD were downloaded from the TCGA database. Subsequently, 323 COAD cases were randomly divided into training and test sets. The differential expression of miRNAs in the high and low TMB groups in the training set was obtained as a signature using the least absolute shrinkage and selection operator (LASSO) logistic regression and verified in the test set. Based on the LASSO method, principal component analysis (PCA), and ROC, we found that the signature was credible because it can discriminate between high and low TMB levels. In addition, the correlation between the 18-miRNA-based signature and immune checkpoints was performed, followed by qRT-PCR, to measure the relative expression of 18 miRNAs in COAD patients. The miRNA-based model had a strong positive correlation with TMB and a weak positive correlation with CTLA4 and CD274 (PD-L1). However, no correlation was observed between the model and SNCA (PD-1). Finally, enrichment analysis of the 18 miRNAs was performed to explore their biological functions. The results demonstrated that 18 miRNAs were involved in the process of immunity and cancer pathways. In conclusion, the 18-miRNA-based signature can effectively predict and discriminate between the different TMB levels of COAD and provide a guide for its treatment with ICIs.

Highlights

Colon adenocarcinoma (COAD) is a common malignant neoplasm of the digestive system
immune checkpoint inhibitors (ICIs) change the treatment of cancer by reactivating T cells tumor cells with higher levels of Tumor mutation burden (TMB) may be more likely to be recognized by the immune system, which in turn triggers a stronger immune response to ICIs [35]
There is a correlation between TMB and the benefits of combined immunotherapy for NSCLC [36]

Summary

Introduction

Colon adenocarcinoma (COAD) is a common malignant neoplasm of the digestive system. Great progress has been made in the treatment of COAD with surgery, chemotherapy, and targeted therapy, the five-year survival rate of patients with advanced COAD remains low. PD-1/PD-L1 ICIs have achieved encouraging results in the treatment of advanced COAD [4,5,6]. Less than 30% of patients exhibit a long-term response to immune checkpoint treatments [7, 8]. This suggests that the expression of PD-L1 is probably not a unique identifying responder, and it is necessary to identify better responders

Methods

Results

Conclusion