Quantification of DNA methylation for carcinogenic risk estimation in patients with non-alcoholic steatohepatitis.
Quantification of DNA methylation for carcinogenic risk estimation in patients with non-alcoholic steatohepatitis.
复制标题
对非酒精性脂肪性肝炎患者的致癌风险估计的DNA甲基化定量。
DOI：
10.1186/s13148-022-01379-4
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发表时间：
2022-12-05
影响因子：
5.7
通讯作者：
Kanai, Yae
中科院分区：
文献类型：
--
作者：
Kuramoto, Junko;Arai, Eri;Fujimoto, Mao;Tian, Ying;Yamada, Yuriko;Yotani, Takuya;Makiuchi, Satomi;Tsuda, Noboru;Ojima, Hidenori;Fukai, Moto;Seki, Yosuke;Kasama, Kazunori;Funahashi, Nobuaki;Udagawa, Haruhide;Nammo, Takao;Yasuda, Kazuki;Taketomi, Akinobu;Kanto, Tatsuya;Kanai, Yae
关键词：
近年来，非酒精性脂肪性肝炎（NASH）已成为肝细胞癌（HCC）的主要病因。作为在早期发现基础上改善NASH相关hcc治疗的一种手段，本研究探讨了NASH患者致癌风险评估的可行性。分析了正常肝组织（NLT）、非HCC患者（NAFL-O）的非癌性肝组织、非HCC患者（NASH- o）的非癌性肝组织、HCC患者（NAFL-W）的非癌性肝组织、HCC患者（NASH- w）的非癌性肝组织和NASH相关HCC的非癌性肝组织。使用了171个组织样本的初始队列和55个组织样本的验证队列。使用Infinium HumanMethylation450 BeadChip进行全基因组DNA甲基化筛选，并使用新开发的阴离子交换柱进行高效液相色谱（HPLC） DNA甲基化定量。基于Infinium分析，相对于NLT样品，NASH-W样品中的4050个CpG位点显示了DNA甲基化的改变。这种在癌前NASH阶段的改变在HCC样本中被遗传或加强。受试者工作特征曲线分析鉴定出415个区分NASH-W和NLT样本的CpG位点，曲线下面积大于0.95。其中，我们重点关注了21个特异性超过85%的CpG位点，甚至可以区分NASH-W和NASH-O样本。这21个CpG位点的DNA甲基化状态能够独立于组织病理学结果（如气球化和纤维化分期）预测HCC的巧合。使用基于高效液相色谱的系统评估了5个候选标记CpG位点的甲基化状态，其中3个位点在验证队列中成功验证了足够的灵敏度和特异性。通过结合包括ZC3H3基因在内的这3个CpG位点，已经出现hcc的NAFL-W和NASH-W样本在验证队列中被证实具有95%的致癌风险。在使用更大的队列进行进一步的前瞻性验证研究后，使用这种基于hplc的DNA甲基化定量系统对NASH患者肝活检标本进行致癌风险评估可能会在临床应用。在线版本包含补充材料，可在10.1186/s13148-022-01379-4获得。
In recent years, non-alcoholic steatohepatitis (NASH) has become the main cause of hepatocellular carcinoma (HCC). As a means of improving the treatment of NASH-related HCCs based on early detection, this study investigated the feasibility of carcinogenic risk estimation in patients with NASH. Normal liver tissue (NLT), non-cancerous liver tissue showing histological findings compatible with non-alcoholic fatty liver from patients without HCC (NAFL-O), non-cancerous liver tissue showing NASH from patients without HCC (NASH-O), non-cancerous liver tissue showing non-alcoholic fatty liver from patients with HCC (NAFL-W), non-cancerous liver tissue showing NASH from patients with HCC (NASH-W) and NASH-related HCC were analyzed. An initial cohort of 171 tissue samples and a validation cohort of 55 tissue samples were used. Genome-wide DNA methylation screening using the Infinium HumanMethylation450 BeadChip and DNA methylation quantification using high-performance liquid chromatography (HPLC) with a newly developed anion-exchange column were performed. Based on the Infinium assay, 4050 CpG sites showed alterations of DNA methylation in NASH-W samples relative to NLT samples. Such alterations at the precancerous NASH stage were inherited by or strengthened in HCC samples. Receiver operating characteristic curve analysis identified 415 CpG sites discriminating NASH-W from NLT samples with area under the curve values of more than 0.95. Among them, we focused on 21 CpG sites showing more than 85% specificity, even for discrimination of NASH-W from NASH-O samples. The DNA methylation status of these 21 CpG sites was able to predict the coincidence of HCC independently from histopathological findings such as ballooning and fibrosis stage. The methylation status of 5 candidate marker CpG sites was assessed using a HPLC-based system, and for 3 of them sufficient sensitivity and specificity were successfully validated in the validation cohort. By combining these 3 CpG sites including the ZC3H3 gene, NAFL-W and NASH-W samples from which HCCs had already arisen were confirmed to show carcinogenic risk with 95% sensitivity in the validation cohort. After a further prospective validation study using a larger cohort, carcinogenic risk estimation in liver biopsy specimens of patients with NASH may become clinically applicable using this HPLC-based system for quantification of DNA methylation. The online version contains supplementary material available at 10.1186/s13148-022-01379-4.
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影响因子：
4.7
作者：
Hamada K;Tian Y;Fujimoto M;Takahashi Y;Kohno T;Tsuta K;Watanabe SI;Yoshida T;Asamura H;Kanai Y;Arai E
通讯作者：
Arai E
影响因子：
3.7
作者：
Fujimoto M;Arai E;Tsumura K;Yotani T;Yamada Y;Takahashi Y;Maeshima AM;Fujimoto H;Yoshida T;Kanai Y
通讯作者：
Kanai Y
影响因子：
3.8
作者：
Arai, Eri;Kanai, Yae
通讯作者：
Kanai, Yae
影响因子：
6.6
作者：
Nakagawa, T;Kanai, Y;Hirohashi, S
通讯作者：
Hirohashi, S
影响因子：
5.7
作者：
Nishiyama, Naotaka;Arai, Eri;Kanai, Yae
通讯作者：
Kanai, Yae