Prognostic Immunity and Therapeutic Sensitivity Analyses Based on Differential Genomic Instability-Associated LncRNAs in Left- and Right-Sided Colon Adenocarcinoma.

Jun-Nan Guo,Tian-Yi Xia,Shen-Hui Deng,Bin-Bin Cui,Yan-Long Liu,Wei-Nan Xue

doi:10.3389/fmolb.2021.668888

Abstract

Background: The purpose of our study was to develop a prognostic risk model based on differential genomic instability-associated (DGIA) long non-coding RNAs (lncRNAs) of left-sided and right-sided colon cancers (LCCs and RCCs); therefore, the prognostic key lncRNAs could be identified.Methods: We adopted two independent gene datasets, corresponding somatic mutation and clinical information from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. Identification of differential DGIA lncRNAs from LCCs and RCCs was conducted with the appliance of “Limma” analysis. Then, we screened out key lncRNAs based on univariate and multivariate Cox proportional hazard regression analysis. Meanwhile, DGIA lncRNAs related prognostic model (DRPM) was established. We employed the DRPM in the model group and internal verification group from TCGA for the purpose of risk grouping and accuracy verification of DRPM. We also verified the accuracy of key lncRNAs with GEO data. Finally, the differences of immune infiltration, functional pathways, and therapeutic sensitivities were analyzed within different risk groups.Results: A total of 123 DGIA lncRNAs were screened out by differential expression analysis. We obtained six DGIA lncRNAs by the construction of DRPM, including AC004009.1, AP003555.2, BOLA3-AS1, NKILA, LINC00543, and UCA1. After the risk grouping by these DGIA lncRNAs, we found the prognosis of the high-risk group (HRG) was significantly worse than that in the low-risk group (LRG) (all p < 0.05). In all TCGA samples and model group, the expression of CD8+ T cells in HRG was lower than that in LRG (all p < 0.05). The functional analysis indicated that there was significant upregulation with regard to pathways related to both genetic instability and immunity in LRG, including cytosolic DNA sensing pathway, response to double-strand RNA, RIG-Ⅰ like receptor signaling pathway, and Toll-like receptor signaling pathway. Finally, we analyzed the difference and significance of key DGIA lncRNAs and risk groups in multiple therapeutic sensitivities.Conclusion: Through the analysis of the DGIA lncRNAs between LCCs and RCCs, we identified six key DGIA lncRNAs. They can not only predict the prognostic risk of patients but also serve as biomarkers for evaluating the differences of genetic instability, immune infiltration, and therapeutic sensitivity.

Highlights

Colon cancer (CC) is one of the most common cancers diagnosed in humans and, globally, there are more than 1.8 million new cases of this disease each year (Siegel et al, 2020; Verkuijl et al, 2021)
In this research, we proposed to create a prognostic model and risk factor clustering containing key long non-coding RNAs (lncRNAs) based on differentially expressed genes and genomic instability in the LCCs and RCCs in The Cancer Genome Atlas (TCGA) database; the leading goal of this study was to analyze the differences in immune infiltration between high- and low-risk groups (HRG and LRG, respectively) and to verify using the Gene Expression Omnibus (GEO) database
We investigated the correlation between these lncRNAs at different stages, and the results indicated that the expression levels of AP003555.2, BOLA3-AS1, NKILA, LINC00543, and UCA1 were significantly different between the least two stages (Figure 4B)

Summary

Introduction

Colon cancer (CC) is one of the most common cancers diagnosed in humans and, globally, there are more than 1.8 million new cases of this disease each year (Siegel et al, 2020; Verkuijl et al, 2021). Some CC patients show a low response and drug resistance (Wu, 2018). Traditional treatments such as surgery, radiotherapy, and chemotherapy are used to suppress cancers, but their longterm effects are difficult to predict. The differences of these phenomena are more obvious in the left-sided and right-sided CCs (LCCs and RCCs, respectively) (Grass et al, 2019). It is well known that the differences in terms of molecular and clinical heterogeneity between LCCs and RCCs are complex, as are their occurrence, development, and response to treatment and prognosis (Blakely et al, 2020). The purpose of our study was to develop a prognostic risk model based on differential genomic instability-associated (DGIA) long non-coding RNAs (lncRNAs) of leftsided and right-sided colon cancers (LCCs and RCCs); the prognostic key lncRNAs could be identified

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Methods

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Discussion

Conclusion