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Plasma cell\u2010free DNA (cfDNA) constitutes a minimally invasive alternative that may better capture tumor\u2010derived profiles from circulating tumor DNA (ctDNA). This study compares the performance and genomic concordance of cfDNA and FFPE tumor DNA in aggressive non\u2010Hodgkin large B\u2010cell lymphoma.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Paired diagnostic FFPE tissue and plasma samples from 15 patients were sequenced with a custom 53\u2010gene panel.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Detection thresholds were empirically guided at 1% variant allele frequency (VAF) for cfDNA and 10% for unpaired FFPE DNA. The median number of cfDNA variants was 6 (interquartile range (IQR): 2\u201311) versus 63 (IQR: 15\u2013250) in FFPE DNA at 1% VAF. Collectively, 102 somatic variants were shared between cfDNA and FFPE DNA with a median of 5 (range: 0\u201323). cfDNA showed a five\u2010fold lower median VAF for shared variants than FFPE DNA (7% vs. 36%, <jats:italic>p<\/jats:italic>\u2009&lt;\u20090.0001). Eighty percent of patients harbored at least one cfDNA variant. A maximum cfDNA recall rate of 83% was observed at FFPE DNA VAF &gt;\u200950%. COSMIC database overlap was twice as high for cfDNA compared to FFPE DNA (22% vs. 11%) at 10% VAF.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>cfDNA has superior specificity for somatic mutation detection but lower sensitivity than FFPE DNA. Modest concordance was demonstrated between the two compartments. Our results support a complementary role of ctDNA in mutational profiling at a 1% VAF threshold in a pragmatic and clinically applicable setup.<\/jats:p><\/jats:sec>","DOI":"10.1111\/ijlh.14454","type":"journal-article","created":{"date-parts":[[2025,3,12]],"date-time":"2025-03-12T02:39:02Z","timestamp":1741747142000},"page":"669-679","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Liquid Biopsy for Enhanced Specificity in Identifying Somatic Mutations in Aggressive Non\u2010Hodgkin Large B\u2010Cell Lymphoma: A Comparative Study of Cell\u2010Free <scp>DNA<\/scp> and Formalin\u2010Fixed Paraffin\u2010Embedded Tissue"],"prefix":"10.1111","volume":"47","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5507-9762","authenticated-orcid":false,"given":"Gayaththri","family":"Vimalathas","sequence":"first","affiliation":[{"name":"Department of Clinical Research University of Southern Denmark  Odense 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