鉴定前列腺癌中细胞质 DNA 感应 cGAS-STING 通路介导的基因特征和分子亚型。

Identification of the cytoplasmic DNA-Sensing cGAS-STING pathway-mediated gene signatures and molecular subtypes in prostate cancer.

机构信息

Department of Urology, West China Hospital of Sichuan University, Sichuan Province, Chengdu, China.

China Agricultural University, Beijing, 100083, China.

出版信息

BMC Cancer. 2024 Jun 14;24(1):732. doi: 10.1186/s12885-024-12492-3.

DOI:10.1186/s12885-024-12492-3

PMID:38877472

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11179326/

Abstract

BACKGROUND

Considering the age relevance of prostate cancer (PCa) and the involvement of the cGAS-STING pathway in aging and cancer, we aim to classify PCa into distinct molecular subtypes and identify key genes from the novel perspective of the cGAS-STING pathway. It is of significance to guide personalized intervention of cancer-targeting therapy based on genetic evidence.

METHODS

The 430 patients with PCa from the TCGA database were included. We integrated 29 key genes involved in cGAS-STING pathway and analyzed differentially expressed genes and biochemical recurrence (BCR)-free survival-related genes. The assessments of tumor stemness and heterogeneity and tumor microenvironment (TME) were conducted to reveal potential mechanisms.

RESULTS

PCa patients were classified into two distinct subtypes using AURKB, TREX1, and STAT6, and subtype 1 had a worse prognosis than subtype 2 (HR: 21.19, p < 0.001). The findings were validated in the MSKCC2010 cohort. Among subtype 1 and subtype 2, the top ten mutation genes were MUC5B, DNAH9, SLC5A10, ZNF462, USP31, SIPA1L3, PLEC, HRAS, MYOM1, and ITGB6. Gene set variation analysis revealed a high enrichment of the E2F target in subtype 1, and gene set enrichment analysis showed significant enrichment of base excision repair, cell cycle, and DNA replication in subtype 1. TME evaluation indicated that subtype 1 had a significantly higher level of T cells follicular helper and a lower level of plasma cells than subtype 2.

CONCLUSIONS

The molecular subtypes mediated by the cGAS-STING pathway and the genetic risk score may aid in identifying potentially high-risk PCa patients who may benefit from pharmacologic therapies targeting the cGAS-STING pathway.

摘要

背景

考虑到前列腺癌（PCa）的年龄相关性以及 cGAS-STING 通路在衰老和癌症中的作用，我们旨在将 PCa 分为不同的分子亚型，并从 cGAS-STING 通路的新视角确定关键基因。这对于基于遗传证据指导癌症靶向治疗的个性化干预具有重要意义。

方法

纳入 TCGA 数据库中的 430 例 PCa 患者。我们整合了 29 个参与 cGAS-STING 通路的关键基因，分析了差异表达基因和生化复发（BCR）无复发生存相关基因。评估肿瘤干性和异质性以及肿瘤微环境（TME），以揭示潜在的机制。

结果

使用 AURKB、TREX1 和 STAT6 将 PCa 患者分为两个不同的亚型，亚型 1 的预后比亚型 2差（HR：21.19，p<0.001）。该发现在 MSKCC2010 队列中得到了验证。在亚型 1 和亚型 2 中，排名前十的突变基因分别为 MUC5B、DNAH9、SLC5A10、ZNF462、USP31、SIPA1L3、PLEC、HRAS、MYOM1 和 ITGB6。基因集变异分析显示，亚型 1 中 E2F 靶基因高度富集，基因集富集分析显示，亚型 1 中碱基切除修复、细胞周期和 DNA 复制显著富集。TME 评估表明，与亚型 2 相比，亚型 1 的滤泡辅助性 T 细胞水平显著更高，浆细胞水平显著更低。