Comprehensive Characterization of Ageing-Relevant Subtypes Associated With Different Tumorigenesis and Tumor Microenvironment in Prostate Cancer.

Liang Huang,Quan Zhu,Weiqing Han,Shusuan Jiang,Yu Xie,Zhenzhou Xu,Zhengyan Tang

doi:10.3389/fmolb.2022.803474

Abstract

Objective: Accumulated evidence demonstrates that ageing is a robust risk factor of prostate cancer prognosis. Herein, we conducted a systematic analysis about ageing-relevant molecules and relevant tumor microenvironment features in prostate cancer. Methods: Transcriptome data, clinical information, and mutational data of prostate cancer patients were retrospectively collected from the Cancer Genome Atlas cohort. In accordance with the expression of specific ageing-relevant genes, prostate cancer patients were clustered with consensus clustering analyses. WGCNA was adopted for determination of subtype-associated co-expression modules and genes. Thereafter, characteristic genes were further screened with random forest algorithm and a prognostic model was conducted with multivariate cox regression analyses. Tumor microenvironment-infiltrating immune cells were estimated with ssGSEA and ESTIMATE. Activities of the cancer immunity cycle and expressions of HLA and immune checkpoint molecules were then quantified across prostate cancer cases. A serious experiment was conducted to investigate the roles of EIF2S2 in prostate tumorigenesis. Results: This study characterized three ageing-relevant subtypes (C1, C2, and C3) with diverse clinical prognosis. Subtype C1 presented the features of low mutational frequency and immune activation; C2 was characterized by stromal and immune activation; and C3 showed immune suppression. An ageing-derived gene signature was conducted, which independently and robustly predicted patients’ prognosis. Additionally, this signature was in relation to immune inactivation. Among the genes in the signature, EIF2S2 triggered proliferation, invasion, and migration of LNCaP and PC-3 cells. Conclusion: Collectively, ageing-relevant molecular subtypes and gene signature might be of great significance to determine clinical outcomes and tumor microenvironment features and immunotherapeutic responses in prostate cancer.

Highlights

Prostate cancer is a frequent malignant tumor of the male genitourinary system across the globe (Culp et al, 2020)
Collectively, ageing-relevant molecular subtypes and gene signature might be of great significance to determine clinical outcomes and tumor microenvironment features and immunotherapeutic responses in prostate cancer
For assessment of the biological functions of ageing-relevant molecules in tumorigenesis and progression of prostate cancer, this study conducted a systematical investigation of the expression of ageing-relevant molecules between prostate tumors and controls in the Cancer Genome Atlas (TCGA) cohort

Summary

Introduction

Prostate cancer is a frequent malignant tumor of the male genitourinary system across the globe (Culp et al, 2020). As estimated, it influences 1/9 men in America and is the second major cause of cancer-related deaths (Swami et al, 2020). It influences 1/9 men in America and is the second major cause of cancer-related deaths (Swami et al, 2020) It represents a heterogeneous malignancy in accordance with clinical, morphological, and molecular levels (Haffner et al, 2021). About 20% of patients with localized prostate cancer will develop regional or distant metastases (Buckup et al, 2021). It is of significance to develop an effective risk stratification as well as favorable therapeutic agents against prostate cancer

Methods

Results

Discussion

Conclusion