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A seven-marker DNA methylation assay for non-invasive early detection of gastric cancer
Background
Gastric cancer (GC) is the fifth most common and fourth most lethal cancer worldwide, with 768,793 deaths in 2020. The patients’ prognosis and survival can be significantly improved by early screening and detection. While endoscopy serves as the gold standard for GC diagnosis and provides sufficient diagnostic power for identifying GC in early stages, this invasive method is costly and of limited feasibility for screening with poor compliance in developing countries with high GC incidence and large populations, e.g., China. On the other hand, currently available non-invasive approaches, including serum-based tumor markers (e.g., CEA and CA19-9), and the combination of serum pepsinogen I and II (PG I/II), gastrin-17 (G-17), anti-Helicobacter pylori IgG antibody tests and clinical information (e.g., score-based prediction rule and ABC method), lack satisfactory sensitivity, especially for early-stage GC screening and diagnosis. We aimed to develop a blood-based DNA methylation assay for GC early detection.
Methods
The study analyzed DNA co-methylation profiles of 38 genomic regions in 128 plasma samples collected from multiple medical centers (52 GC and 76 non-GC samples) using a multiplex methylation-specific quantitative PCR (qPCR) assay. By comparing DNA methylation levels of each region between GC and non-GC groups, the best performing markers were identified and combined to the final seven-marker DNA methylation assay. The clinical performance of the seven-marker assay was further validated in an independent cohort consisting of 193 participants (63 GC and 130 non-GC samples).
Results
Among 38 genomic regions, 11 top ranked regions were combined into the seven-marker DNA methylation assay based on their synergistic diagnostic effects. The assay revealed a superior sensitivity of 87.3% (95% CI: 76.5–94.4%) and comparable specificity of 66.2% (95%CI: 57.3–74.2%) for GC detection in the second cohort as compared to the reported performance of score-based prediction rule using clinical information and PG I, PG II and G-17 test results in Chinese population (sensitivity of 69.6-70.7% and specificity of 66.8-67.8%). In particular, the assay achieved a sensitivity of 80.0% for detecting stage I GC. The assay identified intestinal, diffuse, mixed, and unclassified GC with sensitivities of 100.0%, 100.0%, 85.7%, and 80.6%, respectively.
Conclusions
The seven-marker DNA methylation assay features high GC detection sensitivity, particularly for early-stage GC, providing a potential sensitive and cost-effective GC early screening and diagnostic tool as alternatives to current non-invasive assays.
Legal entity responsible for the study
The authors.
Funding
Science and Technology Planning Project of Guangdong Province, China (Grant NO.2017B020226005), Scheme of Guangzhou for Leading Talents in Innovation and Entrepreneurship (Grant NO.2016007) and Scheme of Guangzhou for Leading Team in Innovation (Grant NO.201909010010), Scheme of Guangzhou Economic and Technological Development District for Leading Talents in Innovation and Entrepreneurship (Grant NO.2017-L152).
Disclosures
W. Ruan: Full / Part-time employment: AnchorDx Medical Co. Ltd. B. Li: Full / Part-time employment: AnchorDx Medical Co., Ltd. K. Cai: Full / Part-time employment: AnchorDx Medical Co., Ltd. Z. Chen: Full / Part-time employment: AnchorDx Medical Co., Ltd., AnchorDx, Inc. M. Bibikova: Shareholder / Stockholder / Stock options: AnchorDx, Illumina; Full / Part-time employment: AnchorDx, Illumina; Officer / Board of Directors: AnchorDx. J. Fan: Leadership role: Anchordx; Shareholder / Stockholder / Stock options: AnchorDx; Full / Part-time employment: AnchorDx; Officer / Board of Directors: Anchordx. All other authors have declared no conflicts of interest.
