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Thus, reported sources of tumour\u2010derived nucleic acids include leukocytes, platelets and apoptotic bodies (AB), as well as large (LEV) and small (SEV) EVs. Despite these competing claims, there has yet to be a standardized comparison of the tumour\u2010derived DNA associated with different components of blood. To address this issue, we collected twenty\u2010three blood samples from seventeen patients with pancreatic cancers of known mutant <jats:italic>KRAS<\/jats:italic> G12 genotype, and divided them into two groups based on the time of patient survival following sampling. After collecting red and white blood cells, we subjected 1\u00a0ml aliquots of platelet rich plasma to differential centrifugation in order to separate the platelets, ABs, LEVs, SEVs and soluble proteins (SP) present. We then confirmed the enrichment of specific blood components in each differential centrifugation fraction using electron microscopy, Western blotting, nanoparticle tracking analysis and bead\u2010based multiplex flow cytometry assays. By targeting wild type and tumour\u2010specific mutant <jats:italic>KRAS<\/jats:italic> alleles using digital PCR, we found that the levels of mutant <jats:italic>KRAS<\/jats:italic> DNA were highest in association with LEVs and SEVs early, and with SEVs and SP late in disease progression. Importantly, we established that SEVs were the most enriched in tumour\u2010derived DNA throughout disease progression, and verified this association using size exclusion chromatography. This work provides important direction for the rapidly expanding field of liquid biopsies by supporting an increased focus on EVs as a source of tumour\u2010derived DNA.<\/jats:p>","DOI":"10.1002\/jev2.12142","type":"journal-article","created":{"date-parts":[[2021,10,1]],"date-time":"2021-10-01T11:06:05Z","timestamp":1633086365000},"source":"Crossref","is-referenced-by-count":46,"title":["Extracellular vesicles are the primary source of blood\u2010borne tumour\u2010derived mutant <i>KRAS<\/i> DNA early in pancreatic cancer"],"prefix":"10.1002","volume":"10","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9246-6235","authenticated-orcid":false,"given":"Daniel W.","family":"Hagey","sequence":"first","affiliation":[{"name":"Department of Laboratory Medicine Karolinska Institutet  Stockholm Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maximilian","family":"Kordes","sequence":"additional","affiliation":[{"name":"Department of Clinical Science Intervention and Technology Karolinska Institutet  Stockholm Sweden"},{"name":"Department of Upper Abdominal Diseases Karolinska University Hospital  Stockholm Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andr\u00e9","family":"G\u00f6rgens","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine Karolinska Institutet  Stockholm Sweden"},{"name":"Institute for Transfusion Medicine University Hospital Essen University of Duisburg Essen  Essen Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Metoboroghene O.","family":"Mowoe","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine Karolinska Institutet  Stockholm Sweden"},{"name":"Institute for Infectious Diseases and Molecular Medicine Division of Chemical and Systems Biology University of Cape Town  Cape Town South Africa"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joel 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