Sui Silei, Xu Caiming, Kanda Mitsuro, Okugawa Yoshinaga, Toiyama Yuji, Park Joon Oh, Hur Hoon, Kim Song Cheol, Taketomi Akinobu, Kodera Yasuhiro, Cheng Xiangdong, Li Man, Goel Ajay
Department of Molecular Diagnostics and Experimental Therapeutics, Beckman Research Institute of City of Hope, Biomedical Research Center, Monrovia, California.
Department of Oncology, The Second Affiliated Hospital of Dalian Medical University, Dalian, China.
JAMA Surg. 2025 Jul 30. doi: 10.1001/jamasurg.2025.2493.
Gastric cancer (GC) is the third leading cause of cancer-related deaths worldwide, primarily attributed to delayed detection. The invasive and cost-prohibitive nature of endoscopy for GC screening highlights the urgent need for noninvasive biomarkers.
To develop an exosome-based diagnostic signature to facilitate blood-based, early detection of patients with GC.
DESIGN, SETTING, AND PARTICIPANTS: This was a multicenter, population-based, retrospective, case-control study that analyzed specimens collected between January 1, 2016, and December 30, 2020. The study encompassed the discovery, training, validation, and evaluation phases of biomarker development. This study was conducted at 4 major referral centers: Nagoya University Hospital in Japan and Ajou University Hospital, Asan Medical Center, and Samsung Medical Center in South Korea, providing a broad representation of advanced clinical care settings. The study included patients with GC, classified according to the TNM (tumor-node-metastasis) classification (8th edition), and controls without disease. Key sociodemographic data, including age and sex, were recorded for all participants. Data were analyzed from October 2022 to July 2024.
Results were obtained from tissue and serum microRNA (miRNA) profiling and expression analysis. Frozen tissue collection and blood draws were conducted intraoperatively, preoperatively, and 3 months postoperatively.
Diagnostic performance of GC detection using an exosome-based miRNA signature.
A total of 809 specimens from 480 patients (mean [SD] age, 61.9 [9.8] years; 336 male [70%]) in the training and validation cohorts were analyzed. A panel of 8 cell-free miRNAs and 10 exosomal miRNAs was initially developed in the discovery phase, which was subsequently reduced using machine learning algorithms to a panel of 8 cell-free and 9 exosomal miRNAs during the training phase. This 17-miRNA signature robustly identified GC with area under the curve (AUC) values of 96.3% (95% CI, 94.3%-98.4%) and 95.3% (95% CI, 92.8%-97.9%) in the training and validation cohorts, respectively. Additionally, 5 overlapping miRNAs were observed between cell-free and exosomal panels and exhibited a comparable efficacy in identifying patients with GC. Finally, we established a 10-miRNA signature (Destinex), which successfully identified early-stage (pT1) GC (AUC = 96.8%; 95% CI, 93.5%-100%). Finally, a significant decrease in miRNA expression levels in postsurgery serum specimens confirmed the robustness of the panel specificity.
Results of this case-control study suggest that the Destinex assay was robust for early detection of GC, highlighting its potential for clinical application in the noninvasive identification of GC.
胃癌（GC）是全球癌症相关死亡的第三大主要原因，主要归因于检测延迟。用于胃癌筛查的内镜检查具有侵入性且成本高昂，这凸显了对非侵入性生物标志物的迫切需求。
开发一种基于外泌体的诊断标志物，以促进基于血液的胃癌患者早期检测。
设计、设置和参与者：这是一项多中心、基于人群的回顾性病例对照研究，分析了2016年1月1日至2020年12月30日期间收集的标本。该研究涵盖了生物标志物开发的发现、训练、验证和评估阶段。该研究在4个主要转诊中心进行：日本名古屋大学医院以及韩国的峨山大学医院、峨山医疗中心和三星医疗中心，广泛代表了先进的临床护理环境。该研究纳入了根据TNM（肿瘤-淋巴结-转移）分类（第8版）分类的胃癌患者以及无疾病的对照。记录了所有参与者的关键社会人口统计学数据，包括年龄和性别。数据于2022年10月至2024年7月进行分析。
从组织和血清微小RNA（miRNA）谱分析和表达分析中获得结果。术中、术前和术后3个月进行冷冻组织采集和血液抽取。
使用基于外泌体的miRNA标志物检测胃癌的诊断性能。
对来自训练和验证队列中480例患者（平均[标准差]年龄，61.9[9.8]岁；336例男性[70%]）的809份标本进行了分析。在发现阶段最初开发了一组8种游离miRNA和10种外泌体miRNA，随后在训练阶段使用机器学习算法将其减少为一组8种游离miRNA和9种外泌体miRNA。这种17-miRNA标志物在训练和验证队列中分别以96.3%（95%CI，94.3%-98.4%）和95.3%（95%CI，92.8%-97.9%）的曲线下面积（AUC）值有力地识别了胃癌。此外，在游离和外泌体组之间观察到5种重叠的miRNA，并且在识别胃癌患者方面表现出相当的功效。最后，我们建立了一种10-miRNA标志物（Destinex），其成功识别了早期（pT1）胃癌（AUC = 96.8%；95%CI, 93.5%-100%）。最后，术后血清标本中miRNA表达水平的显著降低证实了该标志物组特异性的稳健性。
该病例对照研究结果表明，Destinex检测对于胃癌的早期检测具有稳健性，突出了其在胃癌非侵入性识别中的临床应用潜力。
