全面描述 m6A 甲基化及其对肝细胞癌预后、基因组不稳定性和肿瘤微环境的影响。
Comprehensive characterization of m6A methylation and its impact on prognosis, genome instability, and tumor microenvironment in hepatocellular carcinoma.
机构信息
Peking University China-Japan Friendship School of Clinical Medicine, No. 2 Yinghua East Road, Chaoyang District, Beijing, 100029, China.
Department of Gastroenterology, China-Japan Friendship Hospital, Beijing, China.
出版信息
BMC Med Genomics. 2022 Mar 8;15(1):53. doi: 10.1186/s12920-022-01207-x.
BACKGROUND
N6-methyladenosine (m6A) RNA regulation was recently reported to be important in carcinogenesis and cancer development. However, the characteristics of m6A modification and its correlations with clinical features, genome instability, tumor microenvironments (TMEs), and immunotherapy responses in hepatocellular carcinoma (HCC) have not been fully explored.
METHODS
We systematically analyzed the m6A regulator-based expression patterns of 486 patients with HCC from The Cancer Genome Atlas and Gene Expression Omnibus databases, and correlated these patterns with clinical outcomes, somatic mutations, TME cell infiltration, and immunotherapy responses. The m6A score was developed by principal component analysis to evaluate m6A modifications in individual patients.
RESULTS
M6A regulators were dysregulated in HCC samples, among which 18 m6A regulators were identified as risk factors for prognosis. Three m6A regulator-based expression patterns, namely m6A clusters, were determined among HCC patients by m6A regulators with different m6A scores, somatic mutation counts, and specific TME features. Additionally, three distinct m6A regulator-associated gene-based expression patterns were also identified based on prognosis-associated genes that were differentially expressed among the three m6A clusters, showing similar properties as the m6A regulator-based expression patterns. Higher m6A scores were correlated with older age, advanced stages, lower overall survival, higher somatic mutation counts, elevated PD-L1 expression levels, and poorer responses to immune checkpoint inhibitors. The m6A score was validated as an independent and valuable prognostic factor for HCC.
CONCLUSION
M6A modification is correlated with genome instability and TME in HCC. Evaluating m6A regulator-based expression patterns and the m6A score of individual tumors may help identify candidate biomarkers for prognosis prediction and immunotherapeutic strategy selection.
背景
N6-甲基腺苷（m6A）RNA 调控最近被报道在肿瘤发生和发展中很重要。然而，m6A 修饰的特征及其与肝癌（HCC）临床特征、基因组不稳定性、肿瘤微环境（TME）和免疫治疗反应的相关性尚未被充分探索。
方法
我们系统地分析了来自癌症基因组图谱和基因表达综合数据库的 486 例 HCC 患者的 m6A 调节因子表达模式，并将这些模式与临床结局、体细胞突变、TME 细胞浸润和免疫治疗反应相关联。m6A 评分通过主成分分析来评估个体患者的 m6A 修饰。
结果
HCC 样本中的 m6A 调节因子失调，其中 18 个 m6A 调节因子被确定为预后的危险因素。通过 m6A 评分不同的 m6A 调节因子、体细胞突变数量和特定的 TME 特征，确定了 HCC 患者中的三个 m6A 调节因子表达模式，即 m6A 聚类。此外，还根据三个 m6A 聚类中差异表达的预后相关基因，确定了三个不同的基于 m6A 调节因子相关基因的表达模式，它们表现出与 m6A 调节因子表达模式相似的特性。较高的 m6A 评分与年龄较大、分期较晚、总生存率较低、体细胞突变数量较高、PD-L1 表达水平升高以及对免疫检查点抑制剂的反应较差相关。m6A 评分被验证为 HCC 的独立且有价值的预后因素。
结论
m6A 修饰与 HCC 中的基因组不稳定性和 TME 相关。评估个体肿瘤的 m6A 调节因子表达模式和 m6A 评分可能有助于确定用于预后预测和免疫治疗策略选择的候选生物标志物。
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