{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,30]],"date-time":"2026-06-30T19:12:25Z","timestamp":1782846745387,"version":"3.54.5"},"reference-count":65,"publisher":"American Society for Clinical Investigation","issue":"13","license":[{"start":{"date-parts":[[2026,7,1]],"date-time":"2026-07-01T00:00:00Z","timestamp":1782864000000},"content-version":"vor","delay-in-days":43,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000051","name":"NHGRI","doi-asserted-by":"crossref","award":["R56HG012360"],"award-info":[{"award-number":["R56HG012360"]}],"id":[{"id":"10.13039\/100000051","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100007059","name":"Northwestern University","doi-asserted-by":"crossref","award":["startup"],"award-info":[{"award-number":["startup"]}],"id":[{"id":"10.13039\/100007059","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100009947","name":"Merck Sharp & Dohme Corp.","doi-asserted-by":"crossref","award":["conduct of the clinical trial"],"award-info":[{"award-number":["conduct of the clinical trial"]}],"id":[{"id":"10.13039\/100009947","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Cincinnati Children\u2019s Hospital Medical Center","award":["startup"],"award-info":[{"award-number":["startup"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,7,1]]},"abstract":"<jats:sec>\n                    <jats:title>BACKGROUND<\/jats:title>\n                    <jats:p>Minimally invasive biomarkers predicting the immunotherapy response in head and neck squamous cell carcinoma (HNSCC) remain an unmet clinical need.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>METHODS<\/jats:title>\n                    <jats:p>In a prospective, multi-institutional phase II trial, we performed whole-genome sequencing of 185 longitudinal plasma cell-free DNA (cfDNA) samples from 68 patients with locally advanced, surgically resectable HNSCC who received neoadjuvant and adjuvant pembrolizumab. We developed the regional motif diversity score (rMDS), a fragmentomic metric that quantifies the entropy of cfDNA 5\u2032-end motifs across genomic regions.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>RESULTS<\/jats:title>\n                    <jats:p>\n                      Unsupervised analysis showed that rMDS robustly distinguished responders from nonresponders, outperforming established fragmentomic metrics and copy number alterations while remaining independent of technical confounders. Longitudinal rMDS changes localized to regions enriched for immune-, lectin-, and keratinization-related genes \u2014 hallmarks of squamous cell carcinoma \u2014 reflecting tumor\u2013peripheral immunity interplay during treatment. The most dynamic regions clustered at telomere-proximal loci, suggesting a link between telomere biology and cfDNA fragmentation. An rMDS-based machine learning classifier achieved AUC 0.89\u20130.99 across validation settings, with the highest accuracy after treatment, outperforming PD-L1 expression and tumor fraction in matched samples. Predicted responders showed improved disease-free survival (log-rank\n                      <jats:italic>P<\/jats:italic>\n                      = 0.035; HR 2.67, 95% CI 1.03\u20136.92).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>CONCLUSION<\/jats:title>\n                    <jats:p>rMDS represents a biologically meaningful and clinically actionable biomarker for the immunotherapy response in HNSCC, and merits integration into future risk assessment frameworks.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>TRIAL REGISTRATION<\/jats:title>\n                    <jats:p>ClinicalTrials.gov NCT02641093.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>FUNDING<\/jats:title>\n                    <jats:p>National Human Genome Research Institute (NHGRI), NIH grant R56HG012360; startup funds from Cincinnati Children\u2019s Hospital Medical Center, Northwestern University, and Robert H. Lurie Comprehensive Cancer Center; Science Olympiad Alumni Research Grant, Science Olympiad USA Foundation; Merck Sharp &amp; Dohme Corp.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1172\/jci196284","type":"journal-article","created":{"date-parts":[[2026,5,19]],"date-time":"2026-05-19T16:00:37Z","timestamp":1779206437000},"source":"Crossref","is-referenced-by-count":0,"title":["Genome-wide variation in cell-free DNA end-motif entropy predicts immunotherapy response in head and neck cancer"],"prefix":"10.1172","volume":"136","author":[{"given":"Ravi","family":"Bandaru","sequence":"first","affiliation":[{"name":"Department of Biochemistry and Molecular Genetics, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA."},{"name":"Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, Illinois, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hailu","family":"Fu","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Genetics, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA."},{"name":"Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, Illinois, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haizi","family":"Zheng","sequence":"additional","affiliation":[{"name":"Division of Human Genetics, Cincinnati Children\u2019s Hospital Medical Center, Cincinnati, Ohio, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jocelyn","family":"Liang","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Genetics, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA."},{"name":"Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, Illinois, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Li","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Genetics, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA."},{"name":"Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, Illinois, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuchi","family":"Gulati","sequence":"additional","affiliation":[{"name":"Division of Hematology\/Oncology, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Benjamin H.","family":"Hinrichs","sequence":"additional","affiliation":[{"name":"Department of Pathology, University of Cincinnati, Cincinnati, Ohio, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8536-8941","authenticated-orcid":true,"given":"Mingxiang","family":"Teng","sequence":"additional","affiliation":[{"name":"Department of Biostatistics and Bioinformatics, Moffitt Cancer Center, Tampa, Florida, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bin","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA."},{"name":"Division of Biostatistics and Epidemiology, Cincinnati Children\u2019s Hospital Medical Center, Ohio, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masha","family":"Kocherginsky","sequence":"additional","affiliation":[{"name":"Department of Preventive Medicine, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"De-Chen","family":"Lin","sequence":"additional","affiliation":[{"name":"Center for Craniofacial Molecular Biology, Herman Ostrow School of Dentistry, and Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, California, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0421-8483","authenticated-orcid":true,"given":"David A.","family":"Hildeman","sequence":"additional","affiliation":[{"name":"Division of Immunobiology, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francis P.","family":"Worden","sequence":"additional","affiliation":[{"name":"University of Michigan Cancer Center, Ann Arbor, Michigan, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew","family":"Old","sequence":"additional","affiliation":[{"name":"Department of Otolaryngology, Ohio State University, Columbus, Ohio, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Neal E.","family":"Dunlap","sequence":"additional","affiliation":[{"name":"Department of Radiation Oncology, University of Louisville, Louisville, Kentucky, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John M.","family":"Kaczmar","sequence":"additional","affiliation":[{"name":"Division of Hematology\/Oncology, Medical University of South Carolina, Charleston, South Carolina, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maura L.","family":"Gillison","sequence":"additional","affiliation":[{"name":"The University of Texas MD Anderson Cancer Center, Houston, Texas, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dalia","family":"El-Gamal","sequence":"additional","affiliation":[{"name":"Division of Hematology\/Oncology, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Trisha","family":"Wise Draper","sequence":"additional","affiliation":[{"name":"Division of Hematology\/Oncology, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yaping","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Genetics, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA."},{"name":"Robert H. 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