Protumorigenic Role of Elevated Levels of DNA Polymerase Epsilon Predicts an Immune-Suppressive Microenvironment in Clear Cell Renal Cell Carcinoma.

Xiaohui Wu,Shuai Zhao,Wangrui Liu,Dingwei Ye,Shiyin Wei,Haidan Tang,Haineng Huang,Haijia Tang,Hongjing Chen,Chen Ding,Aihetaimujiang Anwaier,Hailiang Zhang,Wen-Hao Xu,Hui Li,Yuan-Yuan Qu

doi:10.3389/fgene.2021.751977

Abstract

Increasing evidence indicates that DNA polymerase epsilon (POLE), which mediates DNA damage repair, is significantly associated with tumor prognosis. This study aimed to analyze POLE expression in tumor samples and its prognostic value for patients with clear cell renal cell carcinoma (ccRCC). We found significantly elevated POLE expression in ccRCC tissues compared with normal tissues of multiple independent cohorts. The POLE expression levels of 523 patients with ccRCC (The Cancer Genome Atlas RNA-seq data) and 179 patients with ccRCC with immunohistochemical data (Fudan University Shanghai Cancer Center) were analyzed to investigate the prognostic implications of POLE expression. Cox regression analyses were implemented to explore the effect of POLE expression on the prognosis of pan-cancer. These findings revealed that elevated POLE expression levels significantly correlated with shorter overall survival (p < 0.001, n = 701) of patients with ccRCC. These data indicate that POLE expression may serve as a prognostic biomarker for cancers. Although POLE mutations were not significantly associated with survival benefits conferred upon patients with ccRCC, a CD4+ T cell-regulated immune microenvironment was significantly activated. Moreover, we found that POLE expression in cancers significantly correlated with an immunosuppressive tumor microenvironment, higher intratumoral heterogeneity, and expression of immune checkpoint genes PDCD1, CTLA4, and CD86, possibly mediated via the JAK/STAT and Notch signaling pathways. In conclusion, the present study is the first to our knowledge to indicate that elevated POLE expression is significantly associated with poor survival and an immune-suppressive tumor microenvironment in ccRCC. These findings suggest that POLE can serve as a biomarker for guiding molecular diagnosis and facilitating the development of novel individual therapeutic strategies for patients with advanced ccRCC.

Highlights

Renal cell carcinoma (RCC) is a common urologic malignancy, accounting for 3% of all malignant tumors (Siegel et al, 2020), and its incidence is increasing annually by 3%, reaching 8–10 million cases worldwide, twice as great as 10 years ago
To determine whether polymerase epsilon (POLE) expression is related to the occurrence and prognosis of clear cell renal cell carcinoma (ccRCC), we first examined five independent ccRCC datasets with available RNA sequencing data from The Cancer Genome Atlas (TCGA) and Oncomine databases
POLE, which is highly expressed in ccRCC tissues, may be used as a promising biomarker for predicting prognosis

Summary

Introduction

Renal cell carcinoma (RCC) is a common urologic malignancy, accounting for 3% of all malignant tumors (Siegel et al, 2020), and its incidence is increasing annually by 3%, reaching 8–10 million cases worldwide, twice as great as 10 years ago. 25%–30% of patients with ccRCC present with metastasis upon initial diagnosis, and the 5-year survival rate of metastatic ccRCC is 32%. Increasing evidence shows that multitargeted therapies employing tyrosine-kinase inhibitors, vascular endothelial growth factor inhibitors, and immune checkpoint therapies (ICTs) confer prolonged survival benefits upon patients with advanced ccRCC (Choueiri and Motzer, 2017). It is vital to identify potential biomarkers or to develop techniques to facilitate early diagnosis and to predict prognosis with the aim of enhancing individualized treatment of patients with ccRCC

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