Department of Colorectal Surgery, Hunan Cancer Hospital and The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, 283 Tongzipo Road, Yuelu District, Changsha, 410013, Hunan, People's Republic of China.
Department of Oncology, The Third Affiliated Hospital of Soochow University, Changzhou, China.
Clin Transl Oncol. 2024 Apr;26(4):891-904. doi: 10.1007/s12094-023-03319-x. Epub 2023 Sep 12.
Recently, enhancer RNAs (eRNAs) have garnered attention as pivotal biomarkers for the onset and progression of cancer. However, the landscape of eRNAs and the implications of eRNA-based molecular subtypes in stage II/III colorectal cancer (CRC) remain largely unexplored.
Comprehensive profiling of eRNAs was conducted on a public stage II/III CRC cohort with total RNA-seq data. We used unsupervised clustering of prognostic eRNAs to establish an eRNA-based subtyping system. Further evaluations included molecular characteristics, immune infiltration, clinical outcomes, and drug responses. Finally, we validated the eRNA-based subtyping system in The Cancer Genome Atlas (TCGA) CRC cohort.
We identified a total of 6453 expressed eRNAs, among which 237 were prognostic. A global upregulation of eRNAs was observed in microsatellite-stable (MSS) CRCs when compared to microsatellite instability-high (MSI-H) CRCs. Through consensus clustering, two novel molecular subtypes, termed Cluster 1(C1) and Cluster 2(C2), were further identified. C1, associated with the activation of epithelial-mesenchymal transition (EMT), hypoxia, and KRAS signaling pathways, showed poorer prognosis. C2, correlated with the canonical CRC subtype, exhibited superior survival outcomes. In addition, C1 showed enrichment with immune infiltration and more sensitivity to immune checkpoint inhibitors.
Our study unravels the molecular heterogeneity of stage II/III CRC at the eRNA level and highlights the potential applications of the novel eRNA-based subtyping system in predicting prognosis and guiding immunotherapy.
最近，增强子 RNA（eRNAs）作为癌症发生和进展的关键生物标志物受到关注。然而，eRNAs 的全景及其在 II/III 期结直肠癌（CRC）中的基于 eRNA 的分子亚型的意义在很大程度上仍未得到探索。
对具有总 RNA-seq 数据的公共 II/III 期 CRC 队列进行了全面的 eRNA 分析。我们使用预后 eRNA 的无监督聚类来建立基于 eRNA 的分型系统。进一步的评估包括分子特征、免疫浸润、临床结局和药物反应。最后，我们在癌症基因组图谱（TCGA）CRC 队列中验证了基于 eRNA 的分型系统。
我们总共鉴定了 6453 个表达的 eRNAs，其中 237 个具有预后意义。与微卫星不稳定高（MSI-H）CRC 相比，微卫星稳定（MSS）CRC 中观察到 eRNAs 的整体上调。通过共识聚类，进一步鉴定了两种新型分子亚型，称为簇 1（C1）和簇 2（C2）。C1 与上皮-间充质转化（EMT）、缺氧和 KRAS 信号通路的激活相关，预后较差。C2 与经典的 CRC 亚型相关，表现出较好的生存结局。此外，C1 表现出与免疫浸润的富集和对免疫检查点抑制剂的更高敏感性。
我们的研究揭示了 II/III 期 CRC 在 eRNA 水平上的分子异质性，并强调了新型基于 eRNA 的分型系统在预测预后和指导免疫治疗方面的潜在应用。
