Alternative splicing and alternative polyadenylation define tumor immune microenvironment and pharmacogenomic landscape in clear cell renal carcinoma

Weimin Zhong; Yulong Wu; Maoshu Zhu; Hongbin Zhong; Chaoqun Huang; Yao Lin; Jiyi Huang

doi:10.1016/j.omtn.2022.01.014

Alternative splicing and alternative polyadenylation define tumor immune microenvironment and pharmacogenomic landscape in clear cell renal carcinoma

Mol Ther Nucleic Acids. 2022 Jan 19:27:927-946. doi: 10.1016/j.omtn.2022.01.014. eCollection 2022 Mar 8.

Authors

Weimin Zhong¹, Yulong Wu², Maoshu Zhu¹, Hongbin Zhong³, Chaoqun Huang¹, Yao Lin⁴, Jiyi Huang³

Affiliations

¹ Central Laboratory at The Fifth Hospital of Xiamen, Xiamen 361101, Fujian Province, China.
² Department of Urology at The Fifth Hospital of Xiamen, Xiamen 361101, Fujian Province, China.
³ Department of Nephrology at The Fifth Hospital of Xiamen, Xiamen 361101, Fujian Province, China.
⁴ Central Laboratory at The Second Affiliated Hospital of Fujian Traditional Chinese Medical University, Innovation and transformation center, Fujian University of Traditional Chinese Medicine, Fuzhou 350122, China.

Abstract

Two major posttranscriptional mechanisms-alternative splicing (AS) and alternative polyadenylation (APA)-have attracted much attention in cancer research. Nevertheless, their roles in clear cell renal carcinoma (ccRCC) are still ill defined. Herein, this study was conducted to uncover the implications of AS and APA events in ccRCC progression. Through consensus molecular clustering analysis, two AS or APA RNA processing phenotypes were separately constructed with distinct prognosis, tumor-infiltrating immune cells, responses to immunotherapy, and chemotherapy. The AS or APA score was constructed to quantify AS or APA RNA processing patterns of individual ccRCCs with principal-component analysis. Both high AS and APA scores were characterized by undesirable survival outcomes, relatively high response to immunotherapy, and low sensitivity to targeted drugs, such as sorafenib and pazopanib. Moreover, several small molecular compounds were predicted for patients with a high AS or APA score. There was a positive correlation between AS and APA scores. Their interplay contributed to poor prognosis and reshaped the tumor immune microenvironment. Collectively, this study is the first to comprehensively analyze two major posttranscriptional events in ccRCC. Our findings uncovered the potential functions of AS and APA events and identified their therapeutic potential in immunotherapy and targeted therapy.

Keywords: alternative polyadenylation; alternative splicing; clear cell renal carcinoma; immunotherapy; prognosis; tumor microenvironment.