Wu Hui-Chen, Yang Hwai-I, Wang Qiao, Chen Chien-Jen, Santella Regina M
Department of Environmental Health Sciences, Mailman School of Public Health of Columbia University, New York, NY 10032, USA.
Genomics Research Center, Academia Sinica, Taipei 11529, Taiwan.
Carcinogenesis. 2017 Oct 1;38(10):1021-1028. doi: 10.1093/carcin/bgx078.
Metastases in the later stages of hepatocellular carcinoma (HCC) cause the majority of deaths associated with the disease, making early detection crucial to patient survival. Risk models assessing HCC risk in the general population can be used for risk stratification for further HCC surveillance, however, none have been validated externally. Methylation of circulating DNA shows potential for non-invasive diagnosis of HCC. We conducted a prospective case-control study nested within a community-based cohort. We measured methylation levels in six genes (CDKN2A, RASSF1A, STEAP4, TBX2, VIM and ZNF154) which were identified in our previous work, using pre-diagnostic plasma DNA from 237 HCC cases and 257 matched controls. We found TBX2 hypermethylation was associated with increased HCC risk, with ORs (95% CI) of 3.2 (1.8-6.0). The associations were mainly among high-risk subjects; among subjects infected with HBV/HCV, the OR (95% CI) of TBX2 methylation was 5.3 (2.2-12.7). Among subjects with high risk scores, the ORs (95% CIs) were 7.8 (1.5-38.6) for Wen-HCC model ≥16, 5.8 (2.2-15.5) for Hung-HCC ≥15 and 7.5 (2.2-26.0) for Michikawa-HCC ≥8. Adding TBX2 methylation improved the accuracy of risk models for a high-risk population, with the area under the curve (AUC) of 76% for Wen-HCC score with TBX2 methylation compared with 69% with Wen-HCC alone. The AUCs were 63% for Hung-HCC score plus TBX2 methylation, and 53% for Hung-HCC alone, 65% for Michikawa-HCC score plus TBX2 methylation and 58% for Michikawa-HCC alone. Our findings suggest the potential increase in risk assessment discrimination and accuracy from incorporation of DNA methylation.
肝细胞癌（HCC）晚期的转移导致了该疾病相关的大多数死亡，因此早期检测对患者生存至关重要。评估普通人群HCC风险的风险模型可用于进一步HCC监测的风险分层，然而，尚无模型经过外部验证。循环DNA甲基化显示出对HCC进行非侵入性诊断的潜力。我们在一个基于社区的队列中开展了一项前瞻性病例对照研究。我们使用237例HCC病例和257例匹配对照的诊断前血浆DNA，测量了我们之前工作中确定的六个基因（CDKN2A、RASSF1A、STEAP4、TBX2、VIM和ZNF154）的甲基化水平。我们发现TBX2高甲基化与HCC风险增加相关，优势比（95%置信区间）为3.2（1.8 - 6.0）。这种关联主要存在于高危人群中；在感染HBV/HCV的人群中，TBX2甲基化的优势比（95%置信区间）为5.3（2.2 - 12.7）。在高风险评分的人群中，对于Wen - HCC模型≥16，优势比（95%置信区间）为7.8（1.5 - 38.6）；对于Hung - HCC≥15，优势比为5.8（2.2 - 15.5）；对于Michikawa - HCC≥8，优势比为7.5（2.2 - 26.0）。添加TBX2甲基化提高了高危人群风险模型的准确性，TBX2甲基化的Wen - HCC评分的曲线下面积（AUC）为76%，而仅Wen - HCC评分时为69%。Hung - HCC评分加TBX2甲基化的AUC为63%，仅Hung - HCC评分为53%；Michikawa - HCC评分加TBX2甲基化的AUC为65%，仅Michikawa - HCC评分为58%。我们的研究结果表明，纳入DNA甲基化可能会提高风险评估的辨别力和准确性。
