Rasmussen Simon Ladefoged, Krarup Henrik Bygum, Sunesen Kåre Gotschalck, Johansen Martin Berg, Stender Mogens Tornby, Pedersen Inge Søkilde, Madsen Poul Henning, Thorlacius-Ussing Ole
Department of Gastrointestinal Surgery, Aalborg University Hospital, Aalborg, Denmark.
Clinical Cancer Research Center, Aalborg University Hospital, Aalborg, Denmark.
PLoS One. 2017 Jul 10;12(7):e0180809. doi: 10.1371/journal.pone.0180809. eCollection 2017.
Colorectal cancer (CRC) is one of the most common cancers in the western world. Screening is an efficient method of reducing cancer-related mortality. Molecular biomarkers for cancer in general and CRC in particular have been proposed, and hypermethylated DNA from stool or blood samples are already implemented as biomarkers for CRC screening. We aimed to evaluate the performance of proven hypermethylated DNA promoter regions as plasma based biomarkers for CRC detection.
We conducted a cross-sectional case-control study of 193 CRC patients and 102 colonoscopy-verified healthy controls. Using methylation specific polymerase chain reaction, we evaluated 30 DNA promoter regions previously found to be CRC specific. We used multivariable logistic regression with stepwise backwards selection, and subsequent leave-pair-out cross validation, to calculate the optimism corrected area under the receiver operating characteristics curve (AUC) for all stage as well as early stage CRC.
None of the individual DNA promoter regions provided an overall sensitivity above 30% at a reasonable specificity. However, seven hypermethylated promoter regions (ALX4, BMP3, NPTX2, RARB, SDC2, SEPT9, and VIM) along with the covariates sex and age yielded an optimism corrected AUC of 0.86 for all stage CRC and 0.85 for early stage CRC. Overall sensitivity for CRC detection was 90.7% at 72.5% specificity using a cut point value of 0.5.
Individual hypermethylated DNA promoter regions have limited value as CRC screening markers. However, a panel of seven hypermethylated promoter regions show great promise as a model for CRC detection.
结直肠癌（CRC）是西方世界最常见的癌症之一。筛查是降低癌症相关死亡率的有效方法。已经提出了一般癌症尤其是CRC的分子生物标志物，并且来自粪便或血液样本的高甲基化DNA已被用作CRC筛查的生物标志物。我们旨在评估已证实的高甲基化DNA启动子区域作为基于血浆的生物标志物用于CRC检测的性能。
我们对193例CRC患者和102例经结肠镜检查证实的健康对照进行了一项横断面病例对照研究。使用甲基化特异性聚合酶链反应，我们评估了先前发现的30个CRC特异性DNA启动子区域。我们使用逐步向后选择的多变量逻辑回归以及随后的留对交叉验证，来计算所有阶段以及早期CRC的受试者操作特征曲线（AUC）下经乐观校正的面积。
在合理的特异性下，没有单个DNA启动子区域的总体敏感性高于30%。然而，七个高甲基化启动子区域（ALX4、BMP3、NPTX2、RARB、SDC2、SEPT9和VIM）以及协变量性别和年龄，对于所有阶段CRC的经乐观校正AUC为0.86，对于早期CRC为0.85。使用切点值0.5时，CRC检测的总体敏感性为90.7%，特异性为72.5%。
单个高甲基化DNA启动子区域作为CRC筛查标志物的价值有限。然而，由七个高甲基化启动子区域组成的一组标志物作为CRC检测模型显示出巨大潜力。
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