Department of Pathology, GROW - School for Oncology and Reproduction, Maastricht University Medical Center, P.O. Box 616, 6200 MD, Maastricht, The Netherlands.
MDxHealth, Inc., Irvine, CA, 92618, USA.
Clin Epigenetics. 2022 Apr 27;14(1):56. doi: 10.1186/s13148-022-01273-z.
DNA methylation biomarkers for early detection, risk stratification and treatment response in cancer have been of great interest over the past decades. Nevertheless, clinical implementation of these biomarkers is limited, as only < 1% of the identified biomarkers is translated into a clinical or commercial setting. Technical factors such as a suboptimal genomic location of the assay and inefficient primer or probe design have been emphasized as important pitfalls in biomarker research. Here, we use eleven diagnostic DNA methylation biomarkers for colorectal cancer (ALX4, APC, CDKN2A, MGMT, MLH1, NDRG4, SDC2, SFRP1, SFRP2, TFPI1 and VIM), previously described in a systematic literature search, to evaluate these pitfalls.
To assess the genomic assay location, the optimal genomic locations according to TCGA data were extracted and compared to the genomic locations used in the published assays for all eleven biomarkers. In addition, all primers and probes were technically evaluated according to several criteria, based on literature and expert opinion. Both assay location and assay design quality varied widely among studies.
Large variation in both assay location and design hinders the development of future DNA methylation biomarkers as well as inter-study comparability.
在过去几十年中，用于癌症早期检测、风险分层和治疗反应的 DNA 甲基化生物标志物引起了极大的关注。然而，这些生物标志物的临床应用受到限制，因为在已确定的生物标志物中，只有<1%被转化为临床或商业应用。技术因素，如检测的基因组位置不理想和引物或探针设计效率低下，已被强调为生物标志物研究中的重要缺陷。在这里，我们使用了之前在系统文献检索中描述的用于结直肠癌的十一个诊断性 DNA 甲基化生物标志物（ALX4、APC、CDKN2A、MGMT、MLH1、NDRG4、SDC2、SFRP1、SFRP2、TFPI1 和 VIM）来评估这些缺陷。
为了评估基因组检测位置，根据 TCGA 数据提取了最佳基因组位置，并将其与所有十一个生物标志物的已发表检测中使用的基因组位置进行了比较。此外，根据文献和专家意见，根据几个标准对所有引物和探针进行了技术评估。研究之间的检测位置和检测设计质量差异很大。
检测位置和设计的巨大差异阻碍了未来 DNA 甲基化生物标志物的发展以及研究之间的可比性。
