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In this paper, we identified and validated tumor-specific markers that can distinguish PCNSL from other CNS tumors in tissues. In a pilot study, we tested these newly identified markers in plasma.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Results<\/jats:title>\n                <jats:p>The Methylation Outlier Detector program was used to identify markers in TCGA dataset of 48 diffuse large B-cell lymphoma (DLBCL) and 656 glioblastomas and lower-grade gliomas. Eight methylated markers clearly distinguished DLBCL from gliomas. Marker performance was verified (ROC-AUC of\u2009\u2265\u20090.989) in samples from several GEO datasets (95 PCNSL; 2112 other primary CNS tumors of 11 types). Next, we developed a novel, efficient assay called Tailed Amplicon Multiplexed-Methylation-Specific PCR (TAM-MSP), which uses two of the methylation markers, cg0504 and <jats:italic>SCG3<\/jats:italic> triplexed with <jats:italic>ACTB<\/jats:italic>. FFPE tissue sections\u00a0(25 cases each) of PCNSL and eight types of other primary CNS tumors were analyzed using TAM-MSP. TAM-MSP distinguished PCNSL from the other primary CNS tumors with 100% accuracy (AUC\u2009=\u20091.00, 95% CI\u20090.95\u20131.00, <jats:italic>P<\/jats:italic>\u2009&lt;\u20090.001). The TAM-MSP assay also detected as few as 5 copies of fully methylated plasma DNA spiked into 0.5\u00a0ml of healthy plasma. In a pilot study of plasma from 15 PCNSL, 5 other CNS tumors and 6 healthy individuals, methylation in cg0504 and <jats:italic>SCG3<\/jats:italic> was detectable in 3\/15 PCNSL samples (20%).<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Conclusion<\/jats:title>\n                <jats:p>The Methylation Outlier Detector program identified methylated markers that distinguish PCNSL from other CNS tumors with accuracy. The high level of accuracy achieved by these markers was validated in tissues by a novel method, TAM-MSP. These studies lay a strong foundation for a liquid biopsy-based test to detect PCNSL-specific circulating tumor DNA.<\/jats:p>\n              <\/jats:sec>","DOI":"10.1186\/s13148-021-01091-9","type":"journal-article","created":{"date-parts":[[2021,5,5]],"date-time":"2021-05-05T08:03:07Z","timestamp":1620201787000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":20,"title":["Methylated markers accurately distinguish primary central nervous system lymphomas (PCNSL) from other CNS tumors"],"prefix":"10.1186","volume":"13","author":[{"given":"Bradley M.","family":"Downs","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wanjun","family":"Ding","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leslie M.","family":"Cope","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher B.","family":"Umbricht","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenge","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huihua","family":"He","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaokang","family":"Ke","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthias","family":"Holdhoff","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chetan","family":"Bettegowda","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weiping","family":"Tao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5656-6703","authenticated-orcid":false,"given":"Saraswati","family":"Sukumar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2021,5,5]]},"reference":[{"key":"1091_CR1","volume-title":"Lymphoma and leukemia of the nervous system","author":"TT Batchelor","year":"2013","unstructured":"Batchelor TT, DeAngelis LM. 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Plasma was collected from newly diagnosed PCNSL at Johns Hopkins Hospital with IRB approval. Informed consent was obtained from all the subjects in this study for use of their samples for research. The healthy plasma samples and the pooled plasma sample were purchased from BioIVT (K<sub>2<\/sub>EDTA plasma, BioIVT, Hicksville, NY).","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"Not applicable.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publications"}},{"value":"S.S. has received research grants, licensing\/royalty fees and consulting fees from Cepheid for the QM-MSP assays. No other authors have disclosed any conflicts of interest.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"104"}}