{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T23:38:23Z","timestamp":1792798703677,"version":"4.5.0"},"reference-count":74,"publisher":"BMJ","issue":"4","license":[{"start":{"date-parts":[[2026,4,15]],"date-time":"2026-04-15T00:00:00Z","timestamp":1776211200000},"content-version":"unspecified","delay-in-days":14,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"name":"Noncommunicable Chronic Diseases-National Science and Technology Major Project","award":["2023ZD0501500"],"award-info":[{"award-number":["2023ZD0501500"]}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82125033, and 82230110"],"award-info":[{"award-number":["82125033, and 82230110"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Clinical Capacity Enhancement Project of the First Affiliated Hospital of Nanjing Medical University, the Pukou District Social Cause Science and Technology Development Project in 2020","award":["S2020-21"],"award-info":[{"award-number":["S2020-21"]}],"id":[{"id":"https:\/\/ror.org\/04py1g812","id-type":"ROR","asserted-by":"crossref"}]},{"name":"Major Project of Science and Technology Development Fund of the Pukou Branch Hospital of Jiangsu Province Hospital (Nanjing Pukou Central Hospital) in 2021","award":["KJ2021-1"],"award-info":[{"award-number":["KJ2021-1"]}],"id":[{"id":"https:\/\/ror.org\/04py1g812","id-type":"ROR","asserted-by":"crossref"}]}],"content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["J Immunother Cancer"],"accepted":{"date-parts":[[2026,4,1]]},"published-print":{"date-parts":[[2026,4]]},"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Advanced gastric cancer (aGC) exhibits substantial heterogeneity in response to combination immunotherapy. Circulating cell-free DNA (cfDNA) enables non-invasive profiling of tumor dynamics and may provide biomarkers for response prediction.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We enrolled 94 patients with aGC undergoing combination immunotherapy and assigned them to a discovery set (n=49) and an internal validation set (n=45). Plasma cfDNA was collected pre-treatment and post-treatment and profiled by low-pass whole-genome sequencing and whole-genome bisulfite sequencing in the discovery set, with targeted bisulfite sequencing used in the validation set.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>The discovery set included 34 responders and 15 non-responders, and the validation set included 30 responders and 15 non-responders. We found that responders showed longer cfDNA, lower cfDNA tumor fraction (median: 0.06 vs 0.01, p&lt;0.001), reduced chromosomal instability (median genomic instability index: 0.026 vs 0.007, p&lt;0.001), and higher global methylation (median: 0.715 vs 0.724, p=0.007). Additionally, the differentially methylated region (DMR) at chr20:25849353-25849490 consistently showed higher methylation in responders in both the discovery (adjusted p=0.006) and validation sets (adjusted p=0.049). A predictor based on this DMR outperformed programmed death-ligand 1 (PD-L1) combined positive score (CPS) with area under the curve (AUCs) of 0.79 (discovery: 95%\u2009CI 0.65 to 0.93)\u2009and 0.72 (validation: 95%\u2009CI 0.54 to 0.91). When integrating PD-L1 CPS with this DMR, the AUCs were 0.81 (discovery: 95%\u2009CI 0.67 to 0.95)\u2009and 0.75 (validation: 95%\u2009CI 0.56 to 0.94), respectively. For on-treatment monitoring, three DMRs increased specifically in responders; among them, increased methylation of chr8:110479193-110480324 and chr8:50891437-50892120 was associated with improved progression-free survival (median: 4.90 vs 11.57 months, p&lt;0.001; median: 5.20 vs 10.20 months, p=0.007).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Integrated cfDNA profiling captures immunotherapy-associated molecular dynamics in aGC. A single pretreatment cfDNA methylation marker (chr20:25849353-25849490) improves response prediction beyond PD-L1 CPS and represents a potential predictive biomarker for combination immunotherapy.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1136\/jitc-2025-013792","type":"journal-article","created":{"date-parts":[[2026,4,15]],"date-time":"2026-04-15T19:05:18Z","timestamp":1776279918000},"page":"e013792","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":1,"title":["Comprehensive molecular characterization of cfDNA as predictive and monitoring biomarkers in advanced gastric cancer receiving immunotherapy"],"prefix":"10.1136","volume":"14","author":[{"given":"Jingshuai","family":"Fang","sequence":"first","affiliation":[{"name":"School of Biological Science and Medical Engineering, Southeast University, Nanjing, Jiangsu, China"},{"name":"Department of Epidemiology, School of Public Health, State Key Laboratory Cultivation 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