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Serum extracellular vesicles (EV) represent a novel liquid biopsy source of tumoral DNA. This study compared copy number alteration (CNA) profiles generated from LC-WGS of formalin-fixed paraffin-embedded (FFPE) tumoral DNA and EV-DNA obtained from cancer patients. Patients with squamous cell carcinoma of the base of tongue (n\u2009=\u20093) and cutaneous squamous cell carcinoma (n\u2009=\u20092) were included. LC-WGS (0.5-1X coverage) was performed on FFPE-DNA and serum EV-DNA. Similarity between CNA profiles was analysed using QDNAseq. FFPE samples had a mean CNA of 31 (range 17\u201350) over 1.9\u2009\u00d7\u200910<jats:sup>9<\/jats:sup> (range 1.0\u20132.6\u2009\u00d7\u200910<jats:sup>9<\/jats:sup>) bp in length, and EV samples had a mean CNA value of 17 (range 7\u201319) over 7.6\u2009\u00d7\u200910<jats:sup>8<\/jats:sup> (range 2.9\u201315\u2009\u00d7\u200910<jats:sup>8<\/jats:sup>) bp in length. A mean of 8 (range 0\u201321) CNA over 5.9\u2009\u00d7\u200910<jats:sup>8<\/jats:sup> (range 1.6\u201314\u2009\u00d7\u200910<jats:sup>8<\/jats:sup>) bp in length was found to overlap between EV and FFPE-derived samples per patient. Although the mean correlation efficient between samples was <jats:italic>r<\/jats:italic>\u2009=\u20090.34 (range \u2212\u00a0.08 to 0.99), this was not statistically significant (<jats:italic>p<\/jats:italic>\u2009&gt;\u20090.05). Regions of highest deletion and duplication in FFPE samples were not well reflected in the EV-DNA. Selected CNA regions in EV-associated DNA were reflective of the primary tumor, however appreciation of global CNA and areas of most significant change was lost. 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