{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T20:58:39Z","timestamp":1792789119276,"version":"4.5.0"},"reference-count":47,"publisher":"MDPI AG","issue":"19","license":[{"start":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T00:00:00Z","timestamp":1790035200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"German Cancer Research Center","id":[{"id":"https:\/\/ror.org\/04cdgtt98","id-type":"ROR","asserted-by":"crossref"}]},{"id":[{"id":"https:\/\/ror.org\/04cdgtt98","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Diagnostics"],"abstract":"<jats:p>Background\/Objectives: Tumor-agnostic plasma ctDNA profiling is used when tumor tissue is unavailable, insufficient, or unrepresentative. We investigated analytical and biological factors associated with oncogenic variant yield. Methods: In the prospective EXMASTER study, plasma cfDNA was analyzed using a 265-gene targeted panel. Technical performance was benchmarked using synthetic reference materials and tumor-informed tissue\u2013plasma comparison. Tumor-agnostic analysis used predefined filtering and oncogenic classification. Results: Forty patients were included; 34 underwent baseline tumor-agnostic plasma profiling. All expected variants were detected in synthetic reference material at the tested nominal allele fractions, including 0.005 (0.5%). In six selected patients, 32 of 33 evaluable tissue-derived variants within the panel footprint were detected in plasma (97.0% variant-level concordance). Tumor-agnostic profiling retained 603 plasma variants, including 74 oncogenic or likely oncogenic variants. Thirty-one of 34 patients (91.2%) had at least one retained plasma variant, whereas 27 of 34 (79.4%) had at least one oncogenic or likely oncogenic variant. No statistically supported association was observed between tissue-derived MATH score and oncogenic variant yield. The correlation between total retained plasma variant burden and oncogenic variant count was considered descriptive because these measures are mathematically dependent. Increasing filtering stringency reduced the retained plasma call set while preserving most tissue-concordant variants. Conclusions: In this exploratory, tumor-heterogeneous cohort, analytical filtering strongly shaped the retained plasma variant set, whereas no statistically supported association was observed between tissue-derived MATH score and oncogenic variant yield. These findings support assay-aware interpretation of plasma sequencing as complementary rather than interchangeable with tissue profiling.<\/jats:p>","DOI":"10.3390\/diagnostics16193077","type":"journal-article","created":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T13:32:12Z","timestamp":1790083932000},"page":"3077","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Analytical and Biological Factors Associated with Oncogenic Variant Yield in Tumor-Agnostic Plasma ctDNA Profiling"],"prefix":"10.3390","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8639-9857","authenticated-orcid":false,"given":"Stephen","family":"George","sequence":"first","affiliation":[{"name":"German Cancer Consortium (DKTK) Partner Site Berlin and German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany"},{"name":"Department of Radiooncology and Radiotherapy, Charit\u00e9 \u2013 Universit\u00e4tsmedizin Berlin, Corporate Member of Freie Universit\u00e4t Berlin and Humboldt-Universit\u00e4t zu Berlin, Charit\u00e9platz 1, 10117 Berlin, Germany"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"conceptualization","vocabulary":"credit"},{"role":"methodology","vocabulary":"credit"},{"role":"formal-analysis","vocabulary":"credit"},{"role":"investigation","vocabulary":"credit"},{"role":"data-curation","vocabulary":"credit"},{"role":"writing-original-draft","vocabulary":"credit"},{"role":"visualization","vocabulary":"credit"},{"role":"project-administration","vocabulary":"credit"}]},{"given":"Lavanya","family":"Ranganathan","sequence":"additional","affiliation":[{"name":"German Cancer Consortium (DKTK) Partner Site Freiburg and German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany"},{"name":"Department of Medicine I, Medical Center \u2013 University of Freiburg, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"methodology","vocabulary":"credit"},{"role":"resources","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-3444-7081","authenticated-orcid":false,"given":"Yizhen","family":"Xiang","sequence":"additional","affiliation":[{"name":"Berlin Institute of Health at Charit\u00e9 \u2013 Universit\u00e4tsmedizin Berlin, Center of Digital Health, 10117 Berlin, Germany"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"methodology","vocabulary":"credit"},{"role":"software","vocabulary":"credit"},{"role":"formal-analysis","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-4049-0846","authenticated-orcid":false,"given":"Alexander","family":"Malt","sequence":"additional","affiliation":[{"name":"Berlin Institute of Health at Charit\u00e9 \u2013 Universit\u00e4tsmedizin Berlin, Center of Digital Health, 10117 Berlin, Germany"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"methodology","vocabulary":"credit"},{"role":"software","vocabulary":"credit"},{"role":"formal-analysis","vocabulary":"credit"}]},{"given":"Shashwat","family":"Sahay","sequence":"additional","affiliation":[{"name":"Berlin Institute of Health at Charit\u00e9 \u2013 Universit\u00e4tsmedizin Berlin, Center of Digital Health, 10117 Berlin, Germany"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"methodology","vocabulary":"credit"},{"role":"software","vocabulary":"credit"},{"role":"formal-analysis","vocabulary":"credit"}]},{"given":"Eva-Maria","family":"Mayr","sequence":"additional","affiliation":[{"name":"Institute of Pathology, School of Medicine and Health, Technical University of Munich (TUM), 81675 Munich, Germany"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"investigation","vocabulary":"credit"}]},{"given":"Florian","family":"Scherer","sequence":"additional","affiliation":[{"name":"German Cancer Consortium (DKTK) Partner Site Freiburg and German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany"},{"name":"Department of Medicine I, Medical Center \u2013 University of Freiburg, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"conceptualization","vocabulary":"credit"},{"role":"supervision","vocabulary":"credit"}]},{"given":"Hanno","family":"Glimm","sequence":"additional","affiliation":[{"name":"Department of Translational Medical Oncology, National Center for Tumor Diseases (NCT), NCT\/University Cancer Center Dresden, a Partnership Between German Cancer Research Center (DKFZ), Faculty of Medicine and University Hospital Carl Gustav Carus, Dresden University of Technology (TUD), and Helmholtz-Zentrum Dresden-Rossendorf, 01307 Dresden, Germany"},{"name":"Translational Medical Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus, Dresden University of Technology (TUD), 01307 Dresden, Germany"},{"name":"German Cancer Consortium (DKTK) Partner Site Dresden, 01307 Dresden, Germany"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"resources","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7907-4595","authenticated-orcid":false,"given":"Stefan","family":"Fr\u00f6hling","sequence":"additional","affiliation":[{"name":"Division of Translational Medical Oncology, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany"},{"name":"National Center for Tumor Diseases (NCT), NCT Heidelberg, a Partnership Between DKFZ and Heidelberg University Hospital, 69120 Heidelberg, Germany"},{"name":"German Cancer Consortium (DKTK) Core Center Heidelberg, 69120 Heidelberg, Germany"},{"name":"Institute of Human Genetics, Heidelberg University, 69120 Heidelberg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"resources","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8426-901X","authenticated-orcid":false,"given":"Naveed","family":"Ishaque","sequence":"additional","affiliation":[{"name":"Berlin Institute of Health at Charit\u00e9 \u2013 Universit\u00e4tsmedizin Berlin, Center of Digital Health, 10117 Berlin, Germany"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"supervision","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5977-5375","authenticated-orcid":false,"given":"Nicole","family":"Pfarr","sequence":"additional","affiliation":[{"name":"Institute of Pathology, School of Medicine and Health, Technical University of Munich (TUM), 81675 Munich, Germany"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"supervision","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0027-7977","authenticated-orcid":false,"given":"Damian T.","family":"Rieke","sequence":"additional","affiliation":[{"name":"German Cancer Consortium (DKTK) Partner Site Berlin and German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany"},{"name":"Comprehensive Cancer Center, Charit\u00e9 \u2013 Universit\u00e4tsmedizin Berlin, Corporate Member of Freie Universit\u00e4t Berlin and Humboldt-Universit\u00e4t zu Berlin, 10117 Berlin, Germany"},{"name":"Department of Hematology, Oncology and Cancer Immunology, Campus Benjamin Franklin, Charit\u00e9 \u2013 Universit\u00e4tsmedizin Berlin, Corporate Member of Freie Universit\u00e4t Berlin and Humboldt-Universit\u00e4t zu Berlin, 12203 Berlin, Germany"},{"name":"National Center for Tumor Diseases (NCT), NCT Berlin, a Partnership Between DKFZ, Charit\u00e9 Universit\u00e4tsmedizin, Berlin Institute of Health at Charit\u00e9 (BIH) and Max Delbr\u00fcck Center (MDC), 10117 Berlin, Germany"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"investigation","vocabulary":"credit"},{"role":"resources","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0512-549X","authenticated-orcid":false,"given":"Ingeborg","family":"Tinhofer","sequence":"additional","affiliation":[{"name":"German Cancer Consortium (DKTK) Partner Site Berlin and German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany"},{"name":"Department of Radiooncology and Radiotherapy, Charit\u00e9 \u2013 Universit\u00e4tsmedizin Berlin, Corporate Member of Freie Universit\u00e4t Berlin and Humboldt-Universit\u00e4t zu Berlin, Charit\u00e9platz 1, 10117 Berlin, Germany"},{"name":"Comprehensive Cancer Center, Charit\u00e9 \u2013 Universit\u00e4tsmedizin Berlin, Corporate Member of Freie Universit\u00e4t Berlin and Humboldt-Universit\u00e4t zu Berlin, 10117 Berlin, Germany"},{"name":"National Center for Tumor Diseases (NCT), NCT Berlin, a Partnership Between DKFZ, Charit\u00e9 Universit\u00e4tsmedizin, Berlin Institute of Health at Charit\u00e9 (BIH) and Max Delbr\u00fcck Center (MDC), 10117 Berlin, Germany"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"conceptualization","vocabulary":"credit"},{"role":"supervision","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"}]}],"member":"1968","published-online":{"date-parts":[[2026,9,22]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"223","DOI":"10.1038\/nrc.2017.7","article-title":"Liquid biopsies come of age: Towards implementation of circulating tumour DNA","volume":"17","author":"Wan","year":"2017","journal-title":"Nat. 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