Key Laboratory of Biological Targeting Diagnosis, Therapy and Rehabilitation of Guangdong Higher Education Institutes, State Key Laboratory of Respiratory Disease, The Fifth Affiliated Hospital, Guangzhou Medical University, The Fifth Clinical College of Guangzhou Medical University, Guangzhou, China.
Sci Rep. 2024 Jul 16;14(1):16404. doi: 10.1038/s41598-024-66744-0.
The epigenetic regulation of N6-methyladenosine (mA) has attracted considerable interest in tumor research, but the potential roles of mA regulator-related genes, remain largely unknown within the context of gastric cancer (GC) and tumor microenvironment (TME). Here, a comprehensive strategy of data mining and computational biology utilizing multiple datasets based on 28 mA regulators (including novel anti-readers) was employed to identify mA regulator-related genes and patterns and elucidate their underlying mechanisms in GC. Subsequently, a scoring system was constructed to evaluate individual prognosis and immunotherapy response. Three distinct mA regulator-related patterns were identified through the unsupervised clustering of 56 mA regulator-related genes (all significantly associated with GC prognosis). TME characterization revealed that these patterns highly corresponded to immune-inflamed, immune-excluded, and immune-desert phenotypes, and their TME characteristics were highly consistent with different clinical outcomes and biological processes. Additionally, an mA-related scoring system was developed to quantify the mA modification pattern of individual samples. Low scores indicated high survival rates and high levels of immune activation, whereas high scores indicated stromal activation and tumor malignancy. Furthermore, the mA-related scores were correlated with tumor mutation loads and various clinical traits, including molecular or histological subtypes and clinical stage or grade, and the score had predictive values across all digestive system tumors and even in all tumor types. Notably, a low score was linked to improved responses to anti-PD-1/L1 and anti-CTLA4 immunotherapy in three independent cohorts. This study has expanded the important role of mA regulator-related genes in shaping TME diversity and clinical/biological traits of GC. The developed scoring system could help develop more effective immunotherapy strategies and personalized treatment guidance.
m6A 甲基化的表观遗传调控在肿瘤研究中引起了广泛关注，但在胃癌（GC）和肿瘤微环境（TME）背景下，mA 调节因子相关基因的潜在作用在很大程度上仍不清楚。在这里，我们采用了一种综合的数据挖掘和计算生物学策略，利用基于 28 个 mA 调节因子（包括新型反读子）的多个数据集，鉴定了 mA 调节因子相关基因和模式，并阐明了它们在 GC 中的潜在机制。随后，构建了一个评分系统来评估个体预后和免疫治疗反应。通过对 56 个 mA 调节因子相关基因（均与 GC 预后显著相关）的无监督聚类，鉴定出三种不同的 mA 调节因子相关模式。TME 特征表明，这些模式与免疫浸润、免疫排斥和免疫荒漠表型高度对应，其 TME 特征与不同的临床结局和生物学过程高度一致。此外，还开发了一个 mA 相关评分系统来量化个体样本的 mA 修饰模式。低评分表明生存率高且免疫激活水平高，而高评分则表明基质激活和肿瘤恶性程度高。此外，mA 相关评分与肿瘤突变负荷和各种临床特征相关，包括分子或组织学亚型以及临床分期或分级，并且在所有消化系统肿瘤甚至所有肿瘤类型中均具有预测价值。值得注意的是，在三个独立队列中，低评分与抗 PD-1/L1 和抗 CTLA4 免疫治疗的反应改善相关。本研究扩展了 mA 调节因子相关基因在塑造 GC 中 TME 多样性和临床/生物学特征方面的重要作用。开发的评分系统可以帮助制定更有效的免疫治疗策略和个性化治疗指导。
