PO.CL01.09 · 临床研究
循环DNA甲基化特征可实现胃肠道癌症的早期检测
Circulating DNA methylation signatures enable early detection of gastrointestinal cancers
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摘要 Abstract
中文摘要
背景：胃肠道癌症的早期检测仍是一项重大临床挑战，原因在于其早期无症状——尤其是胰腺癌和肝癌——加之当前筛查手段灵敏度有限、对高危人群识别不足以及监测可及性方面的持续差异。鉴于胰腺癌和肝癌相关的高死亡率以及结直肠癌的巨大全球发病率，迫切需要更有效的早期诊断策略。
方法与发现：我们此前在胰腺癌患者的循环肿瘤DNA（ctDNA）中鉴定出ZFP30和ZNF781的异常DNA甲基化，在结直肠癌患者中鉴定出TMEM240的异常甲基化，且TMEM240高甲基化还与胃肠道恶性肿瘤的肝转移相关。在本研究中，我们使用qMSP评估了肝细胞癌（HCC）肿瘤组织及配对邻近正常组织中ZFP30/ZNF781和TMEM240的甲基化水平，结果显示所有肿瘤样本中甲基化显著升高。在肝癌患者的血浆游离DNA（cfDNA）中也检测到这些基因的异常甲基化。对TCGA西方队列的分析进一步证实，这些位点在胰腺癌、结直肠癌和肝癌中甲基化持续增加。
验证：我们在独立的亚洲（中国台湾）和西方（美国）队列中验证了这些生物标志物，队列包含101例胃肠道癌症病例——包括胰腺癌、结肠癌、直肠癌和肝癌——以及350例无癌健康受试者。在所分析的所有胃肠道癌症类型中均可检测到ZFP30/ZNF781和/或TMEM240的异常甲基化。
结果：检测灵敏度分别为：早期胰腺癌93.8%，晚期胰腺癌100%，结肠癌90.62%，直肠癌99.0%，肝癌90%，在无癌对照中特异性为98%。
结论：这些结果表明，ZFP30/ZNF781和TMEM240的循环DNA甲基化特征为检测广谱胃肠道癌症提供了一种高灵敏度和高特异性的非侵入性方法，支持其作为早期检测生物标志物的潜在效用。
查看英文原文 English abstract
Background: Early detection of gastrointestinal cancers remains a major clinical challenge due to their asymptomatic early stages-particularly for pancreatic and liver cancers-combined with the limited sensitivity of current screening modalities, inadequate identification of high-risk populations, and persistent disparities in surveillance access. Given the high mortality associated with pancreatic and liver cancers and the substantial global incidence of colorectal cancer, more effective early diagnostic strategies are urgently needed.
Methods and Findings: We previously identified aberrant DNA methylation of ZFP30 and ZNF781 in circulating tumor DNA (ctDNA) from patients with pancreatic cancer, and aberrant methylation of TMEM240 in patients with colorectal cancer, with TMEM240 hypermethylation additionally associated with liver metastasis in gastrointestinal malignancies. In this study, we evaluated methylation levels of ZFP30/ZNF781 and TMEM240 in hepatocellular carcinoma (HCC) tumor tissues and matched adjacent normal tissues using qMSP, revealing significantly elevated methylation in all tumor samples. Aberrant methylation of these genes was also detected in plasma cell-free DNA (cfDNA) from patients with liver cancer. Analysis of TCGA Western cohorts further confirmed consistently increased methylation of these loci in pancreatic, colorectal, and liver cancers.
Validation: We validated these biomarkers in independent Asian (Taiwan) and Western (U.S.) cohorts comprising 101 gastrointestinal cancer cases-including pancreatic, colon, rectal, and liver cancers-and 350 cancer-free healthy subjects. Aberrant methylation of ZFP30/ZNF781 and/or TMEM240 was detectable across all gastrointestinal cancer types analyzed.
Results: Detection sensitivities were 93.8% for early-stage pancreatic cancer, 100% for late-stage pancreatic cancer, 90.62% for colon cancer, 99.0% for rectal cancer, and 90% for liver cancer, with a specificity of 98% in cancer-free controls.
Conclusion: These results demonstrate that circulating DNA methylation signatures of ZFP30/ZNF781 and TMEM240 provide a highly sensitive and specific non-invasive approach for detecting a broad spectrum of gastrointestinal cancers, supporting their potential utility as early detection biomarkers.
利益披露 Disclosure
R. Lin,
EG BioMed US Inc Employment, Stock.