Clinical Experience of Cerebrospinal Fluid–Based Liquid Biopsy Demonstrates Superiority of Cell-Free DNA over Cell Pellet Genomic DNA for Molecular Profiling
Cell-free DNA (cfDNA) from cerebrospinal fluid (CSF) offers unique opportunities for genomic profiling of tumors involving the central nervous system but remains uncommonly used in clinical practice. We describe our clinical experience using cfDNA from CSF for routine molecular testing using Memoria...
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| creator | Bale, Tejus A. Yang, Soo-Ryum Solomon, James P. Nafa, Khedoudja Middha, Sumit Casanova, Jacklyn Sadowska, Justyna Skakodub, Anna Ahmad, Hamza Yu, Helena A. Riely, Greg J. Kris, Mark G. Chandarlapaty, Sarat Rosenblum, Marc K. Gavrilovic, Igor Karajannis, Matthias A. Pentsova, Elena Miller, Alexandra Boire, Adrienne Mellinghoff, Ingo Berger, Michael F. Zehir, Ahmet Ladanyi, Marc Benayed, Ryma Arcila, Maria E. |
| description | Cell-free DNA (cfDNA) from cerebrospinal fluid (CSF) offers unique opportunities for genomic profiling of tumors involving the central nervous system but remains uncommonly used in clinical practice. We describe our clinical experience using cfDNA from CSF for routine molecular testing using Memorial Sloan Kettering Integrated Mutation Profiling of Actionable Cancer Targets (targeting 468 cancer-related genes). In all, 148 cfDNA samples were assessed, comparing results of cfDNA versus genomic DNA (gDNA; gDNA from cell pellets) derived from the same CSF sample and the primary tumor. Of these, 71.6% (106/148) were successfully sequenced. Somatic alterations (mutations and fusions) were observed in 70.8% (75/106) of the samples; 97.3% (73/75) comprised variants confirming central nervous system involvement by a previously diagnosed tumor, 14.7% (11/75) had additional variants consistent with a therapy-related resistance mechanism, and 2.7% (2/75) had variants that independently diagnosed a new primary. Among samples with paired cfDNA and gDNA sequencing results, cfDNA was more frequently positive for at least one mutation [43.6% (55/126) versus 19.8% (25/126)] and harbored 1.6× more mutations (6.94 versus 4.65; P = 0.005), with higher mean variant allele fractions (41.1% versus 13.0%; P |
| doi_str_mv | 10.1016/j.jmoldx.2021.03.001 |
| format | Article |
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We describe our clinical experience using cfDNA from CSF for routine molecular testing using Memorial Sloan Kettering Integrated Mutation Profiling of Actionable Cancer Targets (targeting 468 cancer-related genes). In all, 148 cfDNA samples were assessed, comparing results of cfDNA versus genomic DNA (gDNA; gDNA from cell pellets) derived from the same CSF sample and the primary tumor. Of these, 71.6% (106/148) were successfully sequenced. Somatic alterations (mutations and fusions) were observed in 70.8% (75/106) of the samples; 97.3% (73/75) comprised variants confirming central nervous system involvement by a previously diagnosed tumor, 14.7% (11/75) had additional variants consistent with a therapy-related resistance mechanism, and 2.7% (2/75) had variants that independently diagnosed a new primary. Among samples with paired cfDNA and gDNA sequencing results, cfDNA was more frequently positive for at least one mutation [43.6% (55/126) versus 19.8% (25/126)] and harbored 1.6× more mutations (6.94 versus 4.65; P = 0.005), with higher mean variant allele fractions (41.1% versus 13.0%; P < 0.0001). Among mutation-positive cfDNAs, the corresponding gDNA was frequently negative (44.6%; 25/55) or failed sequencing (17.8%; 9/55). Routine molecular profiling of cfDNA is superior to gDNA from CSF, facilitating the capture of mutations at high variant allele frequency, even in the context of a negative cytology.</description><identifier>ISSN: 1525-1578</identifier><identifier>EISSN: 1943-7811</identifier><identifier>DOI: 10.1016/j.jmoldx.2021.03.001</identifier><identifier>PMID: 33781965</identifier><language>eng</language><publisher>United States: Elsevier Inc</publisher><subject>Cell-Free Nucleic Acids - isolation & purification ; Cerebrospinal Fluid - metabolism ; DNA, Neoplasm - genetics ; DNA, Neoplasm - isolation & purification ; Genomics ; Humans ; Liquid Biopsy - methods ; Mutation ; Regular ; Retrospective Studies</subject><ispartof>The Journal of molecular diagnostics : JMD, 2021-06, Vol.23 (6), p.742-752</ispartof><rights>2021 Association for Molecular Pathology and American Society for Investigative Pathology</rights><rights>Copyright © 2021 Association for Molecular Pathology and American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.</rights><rights>2021 Association for Molecular Pathology and American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved. 2021 Association for Molecular Pathology and American Society for Investigative Pathology</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c463t-55c0d80c5adab5f28f90de7a80fd58c0d777d6a84fbfb724fbff57e952fbf7bd3</citedby><cites>FETCH-LOGICAL-c463t-55c0d80c5adab5f28f90de7a80fd58c0d777d6a84fbfb724fbff57e952fbf7bd3</cites><orcidid>0000-0002-7151-6528 ; 0000-0003-3641-9287 ; 0000-0003-3496-1005 ; 0000-0002-7467-6682 ; 0000-0001-9104-6132 ; 0000-0002-1051-502X ; 0000-0002-0530-0155 ; 0000-0003-4135-6268 ; 0000-0002-9029-1248 ; 0000-0003-4532-8053</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://dx.doi.org/10.1016/j.jmoldx.2021.03.001$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>230,314,778,782,883,3539,27911,27912,45982</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/33781965$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Bale, Tejus A.</creatorcontrib><creatorcontrib>Yang, Soo-Ryum</creatorcontrib><creatorcontrib>Solomon, James P.</creatorcontrib><creatorcontrib>Nafa, Khedoudja</creatorcontrib><creatorcontrib>Middha, Sumit</creatorcontrib><creatorcontrib>Casanova, Jacklyn</creatorcontrib><creatorcontrib>Sadowska, Justyna</creatorcontrib><creatorcontrib>Skakodub, Anna</creatorcontrib><creatorcontrib>Ahmad, Hamza</creatorcontrib><creatorcontrib>Yu, Helena A.</creatorcontrib><creatorcontrib>Riely, Greg J.</creatorcontrib><creatorcontrib>Kris, Mark G.</creatorcontrib><creatorcontrib>Chandarlapaty, Sarat</creatorcontrib><creatorcontrib>Rosenblum, Marc K.</creatorcontrib><creatorcontrib>Gavrilovic, Igor</creatorcontrib><creatorcontrib>Karajannis, Matthias A.</creatorcontrib><creatorcontrib>Pentsova, Elena</creatorcontrib><creatorcontrib>Miller, Alexandra</creatorcontrib><creatorcontrib>Boire, Adrienne</creatorcontrib><creatorcontrib>Mellinghoff, Ingo</creatorcontrib><creatorcontrib>Berger, Michael F.</creatorcontrib><creatorcontrib>Zehir, Ahmet</creatorcontrib><creatorcontrib>Ladanyi, Marc</creatorcontrib><creatorcontrib>Benayed, Ryma</creatorcontrib><creatorcontrib>Arcila, Maria E.</creatorcontrib><title>Clinical Experience of Cerebrospinal Fluid–Based Liquid Biopsy Demonstrates Superiority of Cell-Free DNA over Cell Pellet Genomic DNA for Molecular Profiling</title><title>The Journal of molecular diagnostics : JMD</title><addtitle>J Mol Diagn</addtitle><description>Cell-free DNA (cfDNA) from cerebrospinal fluid (CSF) offers unique opportunities for genomic profiling of tumors involving the central nervous system but remains uncommonly used in clinical practice. We describe our clinical experience using cfDNA from CSF for routine molecular testing using Memorial Sloan Kettering Integrated Mutation Profiling of Actionable Cancer Targets (targeting 468 cancer-related genes). In all, 148 cfDNA samples were assessed, comparing results of cfDNA versus genomic DNA (gDNA; gDNA from cell pellets) derived from the same CSF sample and the primary tumor. Of these, 71.6% (106/148) were successfully sequenced. Somatic alterations (mutations and fusions) were observed in 70.8% (75/106) of the samples; 97.3% (73/75) comprised variants confirming central nervous system involvement by a previously diagnosed tumor, 14.7% (11/75) had additional variants consistent with a therapy-related resistance mechanism, and 2.7% (2/75) had variants that independently diagnosed a new primary. Among samples with paired cfDNA and gDNA sequencing results, cfDNA was more frequently positive for at least one mutation [43.6% (55/126) versus 19.8% (25/126)] and harbored 1.6× more mutations (6.94 versus 4.65; P = 0.005), with higher mean variant allele fractions (41.1% versus 13.0%; P < 0.0001). Among mutation-positive cfDNAs, the corresponding gDNA was frequently negative (44.6%; 25/55) or failed sequencing (17.8%; 9/55). Routine molecular profiling of cfDNA is superior to gDNA from CSF, facilitating the capture of mutations at high variant allele frequency, even in the context of a negative cytology.</description><subject>Cell-Free Nucleic Acids - isolation & purification</subject><subject>Cerebrospinal Fluid - metabolism</subject><subject>DNA, Neoplasm - genetics</subject><subject>DNA, Neoplasm - isolation & purification</subject><subject>Genomics</subject><subject>Humans</subject><subject>Liquid Biopsy - methods</subject><subject>Mutation</subject><subject>Regular</subject><subject>Retrospective Studies</subject><issn>1525-1578</issn><issn>1943-7811</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2021</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9Uctu1DAUtRCIlsIfIOQlmwQ7iePMBqmddgrSQCvRri3Hvi4eOXFqJ6POrv_AB_BvfAmemVJg042v7XPuuY-D0FtKckpo_WGVrzrv9F1ekILmpMwJoc_QIZ1VZcYbSp-nOytYRhlvDtCrGFeJUFV18RIdlGVizGp2iH7One2tkg6f3Q0QLPQKsDd4DgHa4ONg-4Qt3GT1r_sfJzKCxkt7m574xPohbvApdL6PY5AjRPxt2or4YMfNXsW5bBEA8OnXY-zXEHZf-DIdMOJz6H1n1Q40PuAv3oGanAz4MnhjU2c3r9ELI12ENw_xCF0vzq7mn7Llxfnn-fEyU1VdjhljiuiGKCa1bJkpGjMjGrhsiNGsSRjnXNeyqUxrWl5sg2EcZqxIN97q8gh93OsOU9uBVtCniZwYgu1k2Agvrfgf6e13cePXoikIrzhNAu8fBIK_nSCOorNRpTllD36KomCE04oTzhO12lNVWnAMYB7LUCK23oqV2Hsrtt4KUopkXUp792-Lj0l_zPw7A6RFrS0EEdXOUG0DqFFob5-u8Buz-70j</recordid><startdate>202106</startdate><enddate>202106</enddate><creator>Bale, Tejus A.</creator><creator>Yang, Soo-Ryum</creator><creator>Solomon, James P.</creator><creator>Nafa, Khedoudja</creator><creator>Middha, Sumit</creator><creator>Casanova, Jacklyn</creator><creator>Sadowska, Justyna</creator><creator>Skakodub, Anna</creator><creator>Ahmad, Hamza</creator><creator>Yu, Helena A.</creator><creator>Riely, Greg J.</creator><creator>Kris, Mark G.</creator><creator>Chandarlapaty, Sarat</creator><creator>Rosenblum, Marc K.</creator><creator>Gavrilovic, Igor</creator><creator>Karajannis, Matthias A.</creator><creator>Pentsova, Elena</creator><creator>Miller, Alexandra</creator><creator>Boire, Adrienne</creator><creator>Mellinghoff, Ingo</creator><creator>Berger, Michael F.</creator><creator>Zehir, Ahmet</creator><creator>Ladanyi, Marc</creator><creator>Benayed, Ryma</creator><creator>Arcila, Maria E.</creator><general>Elsevier Inc</general><general>American Society for Investigative Pathology</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0002-7151-6528</orcidid><orcidid>https://orcid.org/0000-0003-3641-9287</orcidid><orcidid>https://orcid.org/0000-0003-3496-1005</orcidid><orcidid>https://orcid.org/0000-0002-7467-6682</orcidid><orcidid>https://orcid.org/0000-0001-9104-6132</orcidid><orcidid>https://orcid.org/0000-0002-1051-502X</orcidid><orcidid>https://orcid.org/0000-0002-0530-0155</orcidid><orcidid>https://orcid.org/0000-0003-4135-6268</orcidid><orcidid>https://orcid.org/0000-0002-9029-1248</orcidid><orcidid>https://orcid.org/0000-0003-4532-8053</orcidid></search><sort><creationdate>202106</creationdate><title>Clinical Experience of Cerebrospinal Fluid–Based Liquid Biopsy Demonstrates Superiority of Cell-Free DNA over Cell Pellet Genomic DNA for Molecular Profiling</title><author>Bale, Tejus A. ; 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We describe our clinical experience using cfDNA from CSF for routine molecular testing using Memorial Sloan Kettering Integrated Mutation Profiling of Actionable Cancer Targets (targeting 468 cancer-related genes). In all, 148 cfDNA samples were assessed, comparing results of cfDNA versus genomic DNA (gDNA; gDNA from cell pellets) derived from the same CSF sample and the primary tumor. Of these, 71.6% (106/148) were successfully sequenced. Somatic alterations (mutations and fusions) were observed in 70.8% (75/106) of the samples; 97.3% (73/75) comprised variants confirming central nervous system involvement by a previously diagnosed tumor, 14.7% (11/75) had additional variants consistent with a therapy-related resistance mechanism, and 2.7% (2/75) had variants that independently diagnosed a new primary. 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| identifier | ISSN: 1525-1578 |
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| language | eng |
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| source | Elsevier ScienceDirect Journals Complete - AutoHoldings; MEDLINE; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; Alma/SFX Local Collection |
| subjects | Cell-Free Nucleic Acids - isolation & purification Cerebrospinal Fluid - metabolism DNA, Neoplasm - genetics DNA, Neoplasm - isolation & purification Genomics Humans Liquid Biopsy - methods Mutation Regular Retrospective Studies |
| title | Clinical Experience of Cerebrospinal Fluid–Based Liquid Biopsy Demonstrates Superiority of Cell-Free DNA over Cell Pellet Genomic DNA for Molecular Profiling |
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