Lei Xiaotian, Zhou Dongxun, Wen Ying, Sha Weihong, Ma Juan, Tu Xixiang, Zhai Kewei, Li Caixia, Wang Hong, Tao Jinsheng, Chen Zhiwei, Ruan Weimei, Fan Jian-Bing, Wang Bin, Cui Chunhui
Department of Surgery, Zhujiang Hospital, Southern Medical University Guangzhou, Guangdong, China.
Department of Endoscopy and Gastroenterology, Eastern Hepatobiliary Hospital, Naval Medical University 225 Changhai Road, Shanghai, China.
Am J Cancer Res. 2024 Feb 15;14(2):744-761. doi: 10.62347/TPTQ3682. eCollection 2024.
Colorectal cancer (CRC) and gastric cancer (GC) rank the top five common and lethal cancers worldwide. Early detection can significantly reduce the mortality of CRC and GC. However, current clinical screening methods including invasive endoscopic techniques and noninvasive fecal occult blood test screening tests/fecal immunochemical test have shown low sensitivity or unsatisfactory patient's compliance. Aberrant DNA methylation occurs frequently in tumorigenesis and cell-free DNA (cfDNA) methylation has shown the potential in multi-cancer detection. Herein, we aimed to explore the value of cfDNA methylation in the gastrointestinal cancer detection and develop a noninvasive method for CRC and GC detection. We applied targeted methylation sequencing on a total of 407 plasma samples from patients diagnosed with CRC, GC, and noncancerous gastrointestinal benign diseases (Non-Ca). By analyzing the methylation profiles of 34 CRC, 62 GC and 107 Non-Ca plasma samples in the training set (n=203), we identified 40,110 gastrointestinal cancer-specific markers and 63 tissue of origin (TOO) prediction markers. A new integrated model composed of gastrointestinal cancer detection and TOO prediction for three types of classification of CRC, GC and Non-Ca patients was further developed through logistic regression algorithm and validated in an independent validation set (n=103). The model achieved overall sensitivities of 83% and 81.3% at specificities of 81.5% and 80% for identifying gastrointestinal cancers in the test set and validation set, respectively. The detection sensitivities for GC and CRC were respectively 81.4% and 83.3% in the cohort of the test and validation sets. Among these true positive cancer samples, further TOO prediction showed accuracies of 95.8% and 95.8% for GC patients and accuracies of 86.7% and 93.3% for CRC patients, in test set and validation set, respectively. Collectively, we have identified novel cfDNA methylation biomarkers for CRC and GC detection and shown the promising potential of cfDNA as a noninvasive gastrointestinal cancer detection tool.
结直肠癌（CRC）和胃癌（GC）是全球范围内排名前五的常见致命癌症。早期检测可显著降低CRC和GC的死亡率。然而，目前的临床筛查方法，包括侵入性内镜技术和非侵入性粪便潜血试验/粪便免疫化学检测，已显示出低敏感性或患者依从性不理想。异常DNA甲基化在肿瘤发生过程中频繁出现，游离DNA（cfDNA）甲基化已显示出在多种癌症检测中的潜力。在此，我们旨在探索cfDNA甲基化在胃肠道癌症检测中的价值，并开发一种用于CRC和GC检测的非侵入性方法。我们对来自诊断为CRC、GC和非癌性胃肠道良性疾病（非癌症）患者的总共407份血浆样本进行了靶向甲基化测序。通过分析训练集（n = 203）中34份CRC、62份GC和107份非癌症血浆样本的甲基化谱，我们鉴定出40,110个胃肠道癌症特异性标志物和63个组织起源（TOO）预测标志物。通过逻辑回归算法进一步开发了一种由胃肠道癌症检测和TOO预测组成的新综合模型，用于对CRC、GC和非癌症患者进行三种类型的分类，并在独立验证集（n = 103）中进行了验证。该模型在测试集和验证集中识别胃肠道癌症时，分别在特异性为81.5%和80%的情况下，总体敏感性达到83%和81.3%。在测试集和验证集队列中，GC和CRC的检测敏感性分别为81.4%和83.3%。在这些真阳性癌症样本中，进一步的TOO预测显示，在测试集和验证集中，GC患者的准确率分别为95.8%和95.8%，CRC患者的准确率分别为86.7%和93.3%。总体而言，我们已经鉴定出用于CRC和GC检测的新型cfDNA甲基化生物标志物，并显示出cfDNA作为非侵入性胃肠道癌症检测工具的广阔前景。
