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Prognostic Model for the Risk Stratification of Early and Late Recurrence in Hepatitis B Virus-Related Small Hepatocellular Carcinoma Patients with Global Histone Modifications
Journal of Hepatocellular Carcinoma ( IF 4.2 ) Pub Date : 2021-05-28 , DOI: 10.2147/jhc.s309451 Jin-Ling Duan 1 , Run-Cong Nie 1, 2 , Zhi-Cheng Xiang 1, 3 , Jie-Wei Chen 3 , Min-Hua Deng 1, 2 , Hu Liang 1, 4 , Feng-Wei Wang 1 , Rong-Zhen Luo 3 , Dan Xie 1, 3 , Mu-Yan Cai 1, 3
Journal of Hepatocellular Carcinoma ( IF 4.2 ) Pub Date : 2021-05-28 , DOI: 10.2147/jhc.s309451 Jin-Ling Duan 1 , Run-Cong Nie 1, 2 , Zhi-Cheng Xiang 1, 3 , Jie-Wei Chen 3 , Min-Hua Deng 1, 2 , Hu Liang 1, 4 , Feng-Wei Wang 1 , Rong-Zhen Luo 3 , Dan Xie 1, 3 , Mu-Yan Cai 1, 3
Affiliation
Background and Aim: To assess the profile of global histone modifications in small hepatocellular carcinoma (small HCC) and identify its prognostic value in predicting recurrence.
Methods: The expression profiles of global histone modifications, including H2AK5AC, H2BK20AC, H3K4me2, H3K9AC, H3K18AC, H4K12AC, and H4R3me2, were evaluated with immunohistochemistry in 335 HBV related small HCC patients. Two histone signature classifiers were then developed using least absolute shrinkage and selection operator Cox regression. A nomogram was built using the classifier and independent risk factors. The performances of the classifier and nomogram were assessed by receiver operating characteristic curves.
Results: Histone modifications were more pronounced in tumor tissues than in adjacent liver tissues. In tumor tissues, the risk score built based on the seven-histone signature exhibited satisfactory prediction efficiency, with an AUC = 0.71 (0.63– 0.79) for 2-year survival in the training cohort. Patients with a high risk score had shorter recurrence-free survival than those with a low risk score (HR: 1.96, 95% CI: 1.24– 3.08, p = 0.004; HR: 1.95, 95% CI: 1.12– 3.42, p = 0.019; and HR: 1.97, 95% CI: 1.39– 2.80, p < 0.001 for the training, validation and total cohorts, respectively). Furthermore, the statistical nomogram built using the histone classifier for early recurrence had a C-index = 0.68. In non-neoplastic liver tissues, the hepatic signature based on H3K4me2 and H4R3me2 was related to late recurrence (HR: 2.00, 95% CI: 1.15– 3.48, p = 0.01).
Conclusion: Global histone modifications in tumor and adjacent liver tissues are novel predictors of early and late recurrence, respectively, in HBV-related small HCC patients.
Keywords: small hepatocellular carcinoma, histone modifications, recurrence, LASSO, prognosis
中文翻译：
具有全局组蛋白修饰的乙型肝炎病毒相关小肝癌患者早期和晚期复发风险分层的预后模型
背景和目的：评估小肝细胞癌 (small HCC) 中整体组蛋白修饰的概况，并确定其在预测复发方面的预后价值。
方法：用免疫组化方法在 335 名 HBV 相关的小 HCC 患者中评估了整体组蛋白修饰的表达谱，包括 H2AK5AC、H2BK20AC、H3K4me2、H3K9AC、H3K18AC、H4K12AC 和 H4R3me2。然后使用最小绝对收缩和选择算子 Cox 回归开发了两个组蛋白特征分类器。使用分类器和独立风险因素构建列线图。分类器和列线图的性能通过接收器操作特征曲线进行评估。
结果：组蛋白修饰在肿瘤组织中比在相邻肝组织中更明显。在肿瘤组织中，基于七组蛋白特征构建的风险评分表现出令人满意的预测效率，在训练队列中的 2 年生存期 AUC = 0.71 (0.63–0.79)。高风险评分患者的无复发生存期短于低风险评分患者（HR：1.96，95% CI：1.24-3.08，p = 0.004；HR：1.95，95% CI：1.12-3.42，p = 0.019；和 HR：1.97，95% CI：1.39–2.80，p< 0.001 分别用于训练、验证和总队列）。此外，使用组蛋白分类器构建的用于早期复发的统计列线图的 C 指数 = 0.68。在非肿瘤性肝组织中，基于 H3K4me2 和 H4R3me2 的肝脏特征与晚期复发有关（HR：2.00，95% CI：1.15-3.48，p = 0.01）。
结论：肿瘤和邻近肝组织中的整体组蛋白修饰分别是 HBV 相关小 HCC 患者早期和晚期复发的新预测因子。
关键词：小肝癌，组蛋白修饰，复发，LASSO，预后
更新日期：2021-05-28
Methods: The expression profiles of global histone modifications, including H2AK5AC, H2BK20AC, H3K4me2, H3K9AC, H3K18AC, H4K12AC, and H4R3me2, were evaluated with immunohistochemistry in 335 HBV related small HCC patients. Two histone signature classifiers were then developed using least absolute shrinkage and selection operator Cox regression. A nomogram was built using the classifier and independent risk factors. The performances of the classifier and nomogram were assessed by receiver operating characteristic curves.
Results: Histone modifications were more pronounced in tumor tissues than in adjacent liver tissues. In tumor tissues, the risk score built based on the seven-histone signature exhibited satisfactory prediction efficiency, with an AUC = 0.71 (0.63– 0.79) for 2-year survival in the training cohort. Patients with a high risk score had shorter recurrence-free survival than those with a low risk score (HR: 1.96, 95% CI: 1.24– 3.08, p = 0.004; HR: 1.95, 95% CI: 1.12– 3.42, p = 0.019; and HR: 1.97, 95% CI: 1.39– 2.80, p < 0.001 for the training, validation and total cohorts, respectively). Furthermore, the statistical nomogram built using the histone classifier for early recurrence had a C-index = 0.68. In non-neoplastic liver tissues, the hepatic signature based on H3K4me2 and H4R3me2 was related to late recurrence (HR: 2.00, 95% CI: 1.15– 3.48, p = 0.01).
Conclusion: Global histone modifications in tumor and adjacent liver tissues are novel predictors of early and late recurrence, respectively, in HBV-related small HCC patients.
Keywords: small hepatocellular carcinoma, histone modifications, recurrence, LASSO, prognosis
中文翻译：
具有全局组蛋白修饰的乙型肝炎病毒相关小肝癌患者早期和晚期复发风险分层的预后模型
背景和目的：评估小肝细胞癌 (small HCC) 中整体组蛋白修饰的概况，并确定其在预测复发方面的预后价值。
方法：用免疫组化方法在 335 名 HBV 相关的小 HCC 患者中评估了整体组蛋白修饰的表达谱，包括 H2AK5AC、H2BK20AC、H3K4me2、H3K9AC、H3K18AC、H4K12AC 和 H4R3me2。然后使用最小绝对收缩和选择算子 Cox 回归开发了两个组蛋白特征分类器。使用分类器和独立风险因素构建列线图。分类器和列线图的性能通过接收器操作特征曲线进行评估。
结果：组蛋白修饰在肿瘤组织中比在相邻肝组织中更明显。在肿瘤组织中，基于七组蛋白特征构建的风险评分表现出令人满意的预测效率，在训练队列中的 2 年生存期 AUC = 0.71 (0.63–0.79)。高风险评分患者的无复发生存期短于低风险评分患者（HR：1.96，95% CI：1.24-3.08，p = 0.004；HR：1.95，95% CI：1.12-3.42，p = 0.019；和 HR：1.97，95% CI：1.39–2.80，p< 0.001 分别用于训练、验证和总队列）。此外，使用组蛋白分类器构建的用于早期复发的统计列线图的 C 指数 = 0.68。在非肿瘤性肝组织中，基于 H3K4me2 和 H4R3me2 的肝脏特征与晚期复发有关（HR：2.00，95% CI：1.15-3.48，p = 0.01）。
结论：肿瘤和邻近肝组织中的整体组蛋白修饰分别是 HBV 相关小 HCC 患者早期和晚期复发的新预测因子。
关键词：小肝癌，组蛋白修饰，复发，LASSO，预后
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