用于区分各种肝腺癌(包括肝细胞癌、胆管癌、结肠直肠癌肝转移瘤和胰腺癌肝转移瘤)的 DNA 甲基化生物标记物面板。

IF 4.8 2区 医学 Q1 GENETICS & HEREDITY Clinical Epigenetics Pub Date : 2024-11-04 DOI:10.1186/s13148-024-01766-z
Tina Draškovič, Branislava Ranković, Nina Zidar, Nina Hauptman
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引用次数: 0

摘要

背景:DNA 甲基化生物标志物是诊断和区分肝腺癌最有前途的工具之一,肝腺癌是全球最常见的恶性肿瘤之一。肝腺癌是全球最常见的恶性肿瘤之一,由于预后和治疗方案的不同,对它们进行区分非常重要。本研究旨在验证之前确定的 DNA 甲基化生物标记物,这些标记物能成功区分肝腺癌,包括两种最常见的原发性肝癌--肝细胞癌(HCC)和胆管癌(CCA)、以及两种常见的转移性肝癌:结直肠肝转移瘤(CRLM)和胰腺导管腺癌肝转移瘤(PCLM),并将它们转化为对甲基化敏感的高分辨率熔融(MS-HRM)和数字 PCR(dPCR)平台。研究方法我们的研究纳入了 149 份福尔马林固定、石蜡包埋的组织样本,包括 19 份 CRLM、10 份 PCLM、15 份 HCC、15 份 CCA、15 份结直肠腺癌 (CRC)、15 份胰腺导管腺癌 (PDAC) 及其配对的正常组织样本。样本的甲基化状态是通过 MS-HRM 和甲基化特异性 dPCR 实验确定的。根据 dPCR 数据调整了之前确定的甲基化阈值,并将其应用于 DNA 甲基化阵列数据集(由 The Cancer Genome Atlas (TCGA) 和 Gene Expression Omnibus (GEO) 提供),该数据集最初用于确定所含癌症类型和其他 CRLM 项目的生物标记物。结果表明,在 dPCR 实验中,生物标记物的灵敏度、特异性和诊断准确性均优于对照组:结果:在 dPCR 实验中,DNA 甲基化面板识别 HCC、CCA、CRC、PDAC、CRLM 和 PCLM 的灵敏度分别为 100%、66.7%、100%、86.7%、94.7% 和 80%。这些检测板可区分 HCC、CCA、CRLM、PCLM 和健康肝组织,特异性分别为 100%、100%、97.1% 和 94.9%,诊断准确率分别为 100%、94%、97% 和 93%。利用新增加的 CRLM 项目对相同的生物信息数据进行的重新评估表明,较低的 dPCR 甲基化阈值仍能有效区分所包含的癌症类型。生物信息数据对 HCC、CCA、CRC、PDAC、CRLM 和 PCLM 的灵敏度分别为 88%、64%、97.4%、75.5%、80% 和 84.6%。HCC、CCA、CRLM、PCLM与健康肝组织之间的特异性分别为98%、93%、86.6%和98.2%,诊断准确率分别为94%、91%、86%和98%。此外,我们还证实,所研究的启动子甲基化在原发性 CRC 和 PDAC 的肝转移灶中都得到了保留:结论:癌症特异性甲基化生物标记物面板显示出较高的灵敏度、特异性和诊断准确性,并能利用甲基化特异性 dPCR 区分肝脏的原发性腺癌和转移性腺癌。MS-HRM、dPCR和生物信息学数据之间实现了高度一致,表明生物信息学鉴定的甲基化生物标记物成功地从Illumina Infinium HumanMethylation450 BeadChip (HM450)和llumina MethylationEPIC BeadChip (EPIC)平台转化到了更简单的MS-HRM和dPCR平台。
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DNA methylation biomarker panels for differentiating various liver adenocarcinomas, including hepatocellular carcinoma, cholangiocarcinoma, colorectal liver metastases and pancreatic adenocarcinoma liver metastases.

Background: DNA methylation biomarkers are one of the most promising tools for the diagnosis and differentiation of adenocarcinomas of the liver, which are among the most common malignancies worldwide. Their differentiation is important because of the different prognoses and treatment options. This study aimed to validate previously identified DNA methylation biomarkers that successfully differentiate between liver adenocarcinomas, including the two most common primary liver cancers, hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA), as well as two common metastatic liver cancers, colorectal liver metastases (CRLM) and pancreatic ductal adenocarcinoma liver metastases (PCLM), and translate them to the methylation-sensitive high-resolution melting (MS-HRM) and digital PCR (dPCR) platforms.

Methods: Our study included a cohort of 149 formalin-fixed, paraffin-embedded tissue samples, including 19 CRLMs, 10 PCLMs, 15 HCCs, 15 CCAs, 15 colorectal adenocarcinomas (CRCs), 15 pancreatic ductal adenocarcinomas (PDACs) and their paired normal tissue samples. The methylation status of the samples was experimentally determined by MS-HRM and methylation-specific dPCR. Previously determined methylation threshold were adjusted according to dPCR data and applied to the same DNA methylation array datasets (provided by The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO)) used to originally identify the biomarkers for the included cancer types and additional CRLM projects. The sensitivities, specificities and diagnostic accuracies of the panels for individual cancer types were calculated.

Results: In the dPCR experiment, the DNA methylation panels identified HCC, CCA, CRC, PDAC, CRLM and PCLM with sensitivities of 100%, 66.7%, 100%, 86.7%, 94.7% and 80%, respectively. The panels differentiate between HCC, CCA, CRLM, PCLM and healthy liver tissue with specificities of 100%, 100%, 97.1% and 94.9% and with diagnostic accuracies of 100%, 94%, 97% and 93%, respectively. Reevaluation of the same bioinformatic data with new additional CRLM projects demonstrated that the lower dPCR methylation threshold still effectively differentiates between the included cancer types. The bioinformatic data achieved sensitivities for HCC, CCA, CRC, PDAC, CRLM and PCLM of 88%, 64%, 97.4%, 75.5%, 80% and 84.6%, respectively. Specificities between HCC, CCA, CRLM, PCLM and healthy liver tissue were 98%, 93%, 86.6% and 98.2% and the diagnostic accuracies were 94%, 91%, 86% and 98%, respectively. Moreover, we confirmed that the methylation of the investigated promoters is preserved from primary CRC and PDAC to their liver metastases.

Conclusions: The cancer-specific methylation biomarker panels exhibit high sensitivities, specificities and diagnostic accuracies and enable differentiation between primary and metastatic adenocarcinomas of the liver using methylation-specific dPCR. High concordance was achieved between MS-HRM, dPCR and bioinformatic data, demonstrating the successful translation of bioinformatically identified methylation biomarkers from the Illumina Infinium HumanMethylation450 BeadChip (HM450) and lllumina MethylationEPIC BeadChip (EPIC) platforms to the simpler MS-HRM and dPCR platforms.

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来源期刊
自引率
5.30%
发文量
150
期刊介绍: Clinical Epigenetics, the official journal of the Clinical Epigenetics Society, is an open access, peer-reviewed journal that encompasses all aspects of epigenetic principles and mechanisms in relation to human disease, diagnosis and therapy. Clinical trials and research in disease model organisms are particularly welcome.
期刊最新文献
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