{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,21]],"date-time":"2026-07-21T09:02:21Z","timestamp":1784624541694,"version":"3.55.0"},"reference-count":42,"publisher":"MDPI AG","issue":"14","license":[{"start":{"date-parts":[[2026,7,17]],"date-time":"2026-07-17T00:00:00Z","timestamp":1784246400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Novel blood biomarkers are crucial for HPV-related cancers to overcome the limitations of imaging and biopsies. This review evaluates the diagnostic performance of circulating cell-free DNA (cfDNA) fragmentomic patterns, distinguishing host-genome integrity from specific viral signatures. Following PRISMA guidelines, we searched PubMed, EMBASE, and Web of Science up to February 2026. Methodological quality was assessed via QUADAS-2, and diagnostic performance was synthesized using a random-effects model. From 489 records, six studies (215 patients, 209 controls) met inclusion criteria. Lacking host-derived fragmentomics data, the analysis focused exclusively on the structural size profiles of circulating viral DNA (cfHPV-DNA). Meta-analysis of four cohorts specifically evaluating these viral fragmentation patterns yielded a pooled Diagnostic Odds Ratio (DOR) of 205.73 (95% CI: 44.72\u2013946.38). Specificity was robust (~100%), with high sensitivity (&gt;90%) for macroscopic disease. However, sensitivity decreased in low-tumor-burden cohorts. cfHPV-DNA fragmentation patterns shows promising diagnostic potential for macroscopic HPV-driven malignancies. However, further studies must determine whether fragment sizing truly outperforms binary viral detection and correlates with disease severity. Furthermore, while current assays exploit the analytical simplicity of viral targets, host-derived fragmentomics remains an overlooked compartment that warrants exploration to determine its true clinical value regarding underlying tumor dynamics. Systematic Review Registration: PROSPERO, identifier: CRD420251052768.<\/jats:p>","DOI":"10.3390\/ijms27146372","type":"journal-article","created":{"date-parts":[[2026,7,20]],"date-time":"2026-07-20T07:54:13Z","timestamp":1784534053000},"page":"6372","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Cell-Free DNA Fragmentation Patterns as Biomarkers for Human Papillomavirus-Related Cancers: A Systematic Review of Methodological Diversity and Diagnostic Performance"],"prefix":"10.3390","volume":"27","author":[{"given":"Fernanda","family":"Santos","sequence":"first","affiliation":[{"name":"Faculty of Medicine, Gynecology Department, University of Coimbra, 3004-504 Coimbra, Portugal"},{"name":"Coimbra Academic and Clinical Centre, 3000-075 Coimbra, Portugal"},{"name":"Gynecology Department, ULS\u2014Coimbra Hospital and University Centre of Coimbra, 3004-561 Coimbra, Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0009-3756","authenticated-orcid":false,"given":"Marta S.","family":"Silva","sequence":"additional","affiliation":[{"name":"Gene and Stem Cell Therapies for the Brain Group, Center for Neuroscience and Cell Biology (CNC), 3004-504 Coimbra, Portugal"},{"name":"Vectors, Gene and Cell Therapy Group, Center for Innovative Biomedicine and Biotechnology (CIBB), 3004-504 Coimbra, Portugal"},{"name":"GeneT, Center for Excellence in Gene Therapy in Portugal, University of Coimbra, 3004-504 Coimbra, Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0015-8604","authenticated-orcid":false,"given":"Francisco A.","family":"Caramelo","sequence":"additional","affiliation":[{"name":"Laboratory of Biostatistics and Medical Informatics (LBIM), Faculty of Medicine, University of Coimbra, 3000-548 Coimbra, Portugal"},{"name":"Centre for Innovative Biomedicine and Biotechnology (CIBB), University of Coimbra, 3004-504 Coimbra, Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4076-7516","authenticated-orcid":false,"given":"Magda M.","family":"Santana","sequence":"additional","affiliation":[{"name":"Gene and Stem Cell Therapies for the Brain Group, Center for Neuroscience and Cell Biology (CNC), 3004-504 Coimbra, Portugal"},{"name":"Vectors, Gene and Cell Therapy Group, Center for Innovative Biomedicine and Biotechnology (CIBB), 3004-504 Coimbra, Portugal"},{"name":"GeneT, Center for Excellence in Gene Therapy in Portugal, University of Coimbra, 3004-504 Coimbra, Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rui J.","family":"Nobre","sequence":"additional","affiliation":[{"name":"Gene and Stem Cell Therapies for the Brain Group, Center for Neuroscience and Cell Biology (CNC), 3004-504 Coimbra, Portugal"},{"name":"Vectors, Gene and Cell Therapy Group, Center for Innovative Biomedicine and Biotechnology (CIBB), 3004-504 Coimbra, Portugal"},{"name":"GeneT, Center for Excellence in Gene Therapy in Portugal, University of Coimbra, 3004-504 Coimbra, Portugal"},{"name":"Institute for Interdisciplinary Research (IIIUC), University of Coimbra, 3030-789 Coimbra, Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jorge M. P.","family":"Tomaz","sequence":"additional","affiliation":[{"name":"Blood and Transfusion Medicine Department, ULS\u2014Coimbra Hospital and University Centre of Coimbra, 3004-561 Coimbra, Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5831-3307","authenticated-orcid":false,"given":"Lu\u00eds P.","family":"Almeida","sequence":"additional","affiliation":[{"name":"Gene and Stem Cell Therapies for the Brain Group, Center for Neuroscience and Cell Biology (CNC), 3004-504 Coimbra, Portugal"},{"name":"Vectors, Gene and Cell Therapy Group, Center for Innovative Biomedicine and Biotechnology (CIBB), 3004-504 Coimbra, Portugal"},{"name":"GeneT, Center for Excellence in Gene Therapy in Portugal, University of Coimbra, 3004-504 Coimbra, Portugal"},{"name":"Institute for Interdisciplinary Research (IIIUC), University of Coimbra, 3030-789 Coimbra, Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8396-2667","authenticated-orcid":false,"given":"Margarida","family":"Figueiredo-Dias","sequence":"additional","affiliation":[{"name":"Faculty of Medicine, Gynecology Department, University of Coimbra, 3004-504 Coimbra, Portugal"},{"name":"Coimbra Academic and Clinical Centre, 3000-075 Coimbra, Portugal"},{"name":"Gynecology Department, ULS\u2014Coimbra Hospital and University Centre of Coimbra, 3004-561 Coimbra, Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,7,17]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"21048","DOI":"10.1038\/s41598-025-06700-8","article-title":"HPV cancer burden by anatomical site, country, and region in 2022","volume":"15","author":"Zhang","year":"2025","journal-title":"Sci. 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