Unique genetic profiles from cerebrospinal fluid cell-free DNA in leptomeningeal metastases of EGFR-mutant non-small-cell lung cancer: a new medium of liquid biopsy
Leptomeningeal metastases (LM) are more frequent in non-small-cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) mutations. Due to limited access to leptomeningeal lesions, the purpose of this study was to explore the potential role of cerebrospinal fluid (CSF) as a source of liqu...
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| Veröffentlicht in: | Annals of oncology 2018-04, Vol.29 (4), p.945-952 |
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| creator | Li, Y.S. Jiang, B.Y. Yang, J.J. Zhang, X.C. Zhang, Z. Ye, J.Y. Zhong, W.Z. Tu, H.Y. Chen, H.J. Wang, Z. Xu, C.R. Wang, B.C. Du, H.J. Chuai, S. Han-Zhang, H. Su, J. Zhou, Q. Yang, X.N. Guo, W.B. Yan, H.H. Liu, Y.H. Yan, L.X. Huang, B. Zheng, M.M. Wu, Y.L. |
| description | Leptomeningeal metastases (LM) are more frequent in non-small-cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) mutations. Due to limited access to leptomeningeal lesions, the purpose of this study was to explore the potential role of cerebrospinal fluid (CSF) as a source of liquid biopsy in patients with LM.
Primary tumor, CSF, and plasma in NSCLC with LM were tested by next-generation sequencing. In total, 45 patients with suspected LM underwent lumbar puncture, and those with EGFR mutations diagnosed with LM were enrolled.
A total of 28 patients were enrolled in this cohort; CSF and plasma were available in 26 patients, respectively. Driver genes were detected in 100% (26/26), 84.6% (22/26), and 73.1% (19/26) of samples comprising CSF cell-free DNA (cfDNA), CSF precipitates, and plasma, respectively; 92.3% (24/26) of patients had much higher allele fractions in CSF cfDNA than the other two media. Unique genetic profiles were captured in CSF cfDNA compared with those in plasma and primary tissue. Multiple copy number variations (CNVs) were mainly identified in CSF cfDNA, and MET copy number gain identified in 47.8% (11/23) of patients was the most frequent one, while other CNVs included ERBB2, KRAS, ALK, and MYC. Moreover, loss of heterozygosity (LOH) of TP53 was identified in 73.1% (19/26) CSF cfDNA, which was much higher than that in plasma (2/26, 7.7%; P |
| doi_str_mv | 10.1093/annonc/mdy009 |
| format | Article |
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Primary tumor, CSF, and plasma in NSCLC with LM were tested by next-generation sequencing. In total, 45 patients with suspected LM underwent lumbar puncture, and those with EGFR mutations diagnosed with LM were enrolled.
A total of 28 patients were enrolled in this cohort; CSF and plasma were available in 26 patients, respectively. Driver genes were detected in 100% (26/26), 84.6% (22/26), and 73.1% (19/26) of samples comprising CSF cell-free DNA (cfDNA), CSF precipitates, and plasma, respectively; 92.3% (24/26) of patients had much higher allele fractions in CSF cfDNA than the other two media. Unique genetic profiles were captured in CSF cfDNA compared with those in plasma and primary tissue. Multiple copy number variations (CNVs) were mainly identified in CSF cfDNA, and MET copy number gain identified in 47.8% (11/23) of patients was the most frequent one, while other CNVs included ERBB2, KRAS, ALK, and MYC. Moreover, loss of heterozygosity (LOH) of TP53 was identified in 73.1% (19/26) CSF cfDNA, which was much higher than that in plasma (2/26, 7.7%; P<0.001). There was a trend towards a higher frequency of concomitant resistance mutations in patients with TP53 LOH than those without (70.6% versus 33.3%; P=0.162). EGFR T790M was identified in CSF cfDNA of 30.4% (7/23) of patients who experienced TKI progression.
CSF cfDNA could reveal the unique genetic profiles of LM and should be considered as the most representative liquid biopsy medium for LM in EGFR-mutant NSCLC.</description><identifier>ISSN: 0923-7534</identifier><identifier>EISSN: 1569-8041</identifier><identifier>DOI: 10.1093/annonc/mdy009</identifier><identifier>PMID: 29346604</identifier><language>eng</language><publisher>England: Elsevier Ltd</publisher><subject>Adult ; Aged ; Aged, 80 and over ; Carcinoma, Non-Small-Cell Lung - cerebrospinal fluid ; Carcinoma, Non-Small-Cell Lung - genetics ; Carcinoma, Non-Small-Cell Lung - pathology ; Cell-Free Nucleic Acids - cerebrospinal fluid ; cerebrospinal fluid ; cfDNA ; DNA Copy Number Variations ; EGFR mutations ; Female ; Gene Expression Profiling ; Genes, erbB-1 ; Genes, p53 ; Humans ; leptomeningeal metastases ; liquid biopsy ; Liquid Biopsy - methods ; Loss of Heterozygosity ; Lung Neoplasms - cerebrospinal fluid ; Lung Neoplasms - genetics ; Lung Neoplasms - pathology ; Male ; Meningeal Neoplasms - cerebrospinal fluid ; Meningeal Neoplasms - pathology ; Meningeal Neoplasms - secondary ; Middle Aged ; Mutation ; non-small-cell lung cancer ; Spinal Puncture</subject><ispartof>Annals of oncology, 2018-04, Vol.29 (4), p.945-952</ispartof><rights>2017 THE AUTHORS</rights><rights>The Author(s) 2018. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For Permissions, please email: journals.permissions@oup.com. 2018</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c479t-151a8e27fe79f58f271f2c212ef3ab2f1dc62a8007666e8469fe7c49ed77c91f3</citedby><cites>FETCH-LOGICAL-c479t-151a8e27fe79f58f271f2c212ef3ab2f1dc62a8007666e8469fe7c49ed77c91f3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,776,780,27901,27902</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/29346604$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Li, Y.S.</creatorcontrib><creatorcontrib>Jiang, B.Y.</creatorcontrib><creatorcontrib>Yang, J.J.</creatorcontrib><creatorcontrib>Zhang, X.C.</creatorcontrib><creatorcontrib>Zhang, Z.</creatorcontrib><creatorcontrib>Ye, J.Y.</creatorcontrib><creatorcontrib>Zhong, W.Z.</creatorcontrib><creatorcontrib>Tu, H.Y.</creatorcontrib><creatorcontrib>Chen, H.J.</creatorcontrib><creatorcontrib>Wang, Z.</creatorcontrib><creatorcontrib>Xu, C.R.</creatorcontrib><creatorcontrib>Wang, B.C.</creatorcontrib><creatorcontrib>Du, H.J.</creatorcontrib><creatorcontrib>Chuai, S.</creatorcontrib><creatorcontrib>Han-Zhang, H.</creatorcontrib><creatorcontrib>Su, J.</creatorcontrib><creatorcontrib>Zhou, Q.</creatorcontrib><creatorcontrib>Yang, X.N.</creatorcontrib><creatorcontrib>Guo, W.B.</creatorcontrib><creatorcontrib>Yan, H.H.</creatorcontrib><creatorcontrib>Liu, Y.H.</creatorcontrib><creatorcontrib>Yan, L.X.</creatorcontrib><creatorcontrib>Huang, B.</creatorcontrib><creatorcontrib>Zheng, M.M.</creatorcontrib><creatorcontrib>Wu, Y.L.</creatorcontrib><title>Unique genetic profiles from cerebrospinal fluid cell-free DNA in leptomeningeal metastases of EGFR-mutant non-small-cell lung cancer: a new medium of liquid biopsy</title><title>Annals of oncology</title><addtitle>Ann Oncol</addtitle><description>Leptomeningeal metastases (LM) are more frequent in non-small-cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) mutations. Due to limited access to leptomeningeal lesions, the purpose of this study was to explore the potential role of cerebrospinal fluid (CSF) as a source of liquid biopsy in patients with LM.
Primary tumor, CSF, and plasma in NSCLC with LM were tested by next-generation sequencing. In total, 45 patients with suspected LM underwent lumbar puncture, and those with EGFR mutations diagnosed with LM were enrolled.
A total of 28 patients were enrolled in this cohort; CSF and plasma were available in 26 patients, respectively. Driver genes were detected in 100% (26/26), 84.6% (22/26), and 73.1% (19/26) of samples comprising CSF cell-free DNA (cfDNA), CSF precipitates, and plasma, respectively; 92.3% (24/26) of patients had much higher allele fractions in CSF cfDNA than the other two media. Unique genetic profiles were captured in CSF cfDNA compared with those in plasma and primary tissue. Multiple copy number variations (CNVs) were mainly identified in CSF cfDNA, and MET copy number gain identified in 47.8% (11/23) of patients was the most frequent one, while other CNVs included ERBB2, KRAS, ALK, and MYC. Moreover, loss of heterozygosity (LOH) of TP53 was identified in 73.1% (19/26) CSF cfDNA, which was much higher than that in plasma (2/26, 7.7%; P<0.001). There was a trend towards a higher frequency of concomitant resistance mutations in patients with TP53 LOH than those without (70.6% versus 33.3%; P=0.162). EGFR T790M was identified in CSF cfDNA of 30.4% (7/23) of patients who experienced TKI progression.
CSF cfDNA could reveal the unique genetic profiles of LM and should be considered as the most representative liquid biopsy medium for LM in EGFR-mutant NSCLC.</description><subject>Adult</subject><subject>Aged</subject><subject>Aged, 80 and over</subject><subject>Carcinoma, Non-Small-Cell Lung - cerebrospinal fluid</subject><subject>Carcinoma, Non-Small-Cell Lung - genetics</subject><subject>Carcinoma, Non-Small-Cell Lung - pathology</subject><subject>Cell-Free Nucleic Acids - cerebrospinal fluid</subject><subject>cerebrospinal fluid</subject><subject>cfDNA</subject><subject>DNA Copy Number Variations</subject><subject>EGFR mutations</subject><subject>Female</subject><subject>Gene Expression Profiling</subject><subject>Genes, erbB-1</subject><subject>Genes, p53</subject><subject>Humans</subject><subject>leptomeningeal metastases</subject><subject>liquid biopsy</subject><subject>Liquid Biopsy - methods</subject><subject>Loss of Heterozygosity</subject><subject>Lung Neoplasms - cerebrospinal fluid</subject><subject>Lung Neoplasms - genetics</subject><subject>Lung Neoplasms - pathology</subject><subject>Male</subject><subject>Meningeal Neoplasms - cerebrospinal fluid</subject><subject>Meningeal Neoplasms - pathology</subject><subject>Meningeal Neoplasms - secondary</subject><subject>Middle Aged</subject><subject>Mutation</subject><subject>non-small-cell lung cancer</subject><subject>Spinal Puncture</subject><issn>0923-7534</issn><issn>1569-8041</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2018</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFkUFrFTEUhYMo9lldupUs3cQmmXnJxF2pbRWKhWLXQ17m5hGZJGMyo7z_4w_1PqbqqhQCgfCdc2_OIeSt4B8EN82ZTSkndxaHA-fmGdmIrTKs4614TjbcyIbpbdOekFe1fuecKyPNS3IiTdMqxdsN-X2fwo8F6B4SzMHRqWQfRqjUlxypgwK7kusUkh2pH5cw4Ns4Ml8A6Kev5zQkOsI05wgppD0gFWG2FQ96ZE8vr6_uWFxmm2aKi7IaLcqPHnRc0p46m3DIR2ppgl-oHcISj7oRt8Jhu5CnenhNXng7VnjzcJ-S-6vLbxef2c3t9ZeL8xvmWm1mJrbCdiC1B238tvNSCy-dFBJ8Y3fSi8EpaTvOtVIKulYZJF1rYNDaGeGbU_J-9cUUMJQ69zHU4642QV5qL0xnFJddIxBlK-ownlrA91MJ0ZZDL3h_LKZfi-nXYpB_92C97PCX_-i_TfyfnZfpSS-9ooBZ_AxQ-uoCYI5DKODmfsjhEeUfNvOwHA</recordid><startdate>201804</startdate><enddate>201804</enddate><creator>Li, Y.S.</creator><creator>Jiang, B.Y.</creator><creator>Yang, J.J.</creator><creator>Zhang, X.C.</creator><creator>Zhang, Z.</creator><creator>Ye, J.Y.</creator><creator>Zhong, W.Z.</creator><creator>Tu, H.Y.</creator><creator>Chen, H.J.</creator><creator>Wang, Z.</creator><creator>Xu, C.R.</creator><creator>Wang, B.C.</creator><creator>Du, H.J.</creator><creator>Chuai, S.</creator><creator>Han-Zhang, H.</creator><creator>Su, J.</creator><creator>Zhou, Q.</creator><creator>Yang, X.N.</creator><creator>Guo, W.B.</creator><creator>Yan, H.H.</creator><creator>Liu, Y.H.</creator><creator>Yan, L.X.</creator><creator>Huang, B.</creator><creator>Zheng, M.M.</creator><creator>Wu, Y.L.</creator><general>Elsevier Ltd</general><general>Oxford University Press</general><scope>6I.</scope><scope>AAFTH</scope><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></search><sort><creationdate>201804</creationdate><title>Unique genetic profiles from cerebrospinal fluid cell-free DNA in leptomeningeal metastases of EGFR-mutant non-small-cell lung cancer: a new medium of liquid biopsy</title><author>Li, Y.S. ; Jiang, B.Y. ; Yang, J.J. ; Zhang, X.C. ; Zhang, Z. ; Ye, J.Y. ; Zhong, W.Z. ; Tu, H.Y. ; Chen, H.J. ; Wang, Z. ; Xu, C.R. ; Wang, B.C. ; Du, H.J. ; Chuai, S. ; Han-Zhang, H. ; Su, J. ; Zhou, Q. ; Yang, X.N. ; Guo, W.B. ; Yan, H.H. ; Liu, Y.H. ; Yan, L.X. ; Huang, B. ; Zheng, M.M. ; Wu, Y.L.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c479t-151a8e27fe79f58f271f2c212ef3ab2f1dc62a8007666e8469fe7c49ed77c91f3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2018</creationdate><topic>Adult</topic><topic>Aged</topic><topic>Aged, 80 and over</topic><topic>Carcinoma, Non-Small-Cell Lung - cerebrospinal fluid</topic><topic>Carcinoma, Non-Small-Cell Lung - genetics</topic><topic>Carcinoma, Non-Small-Cell Lung - pathology</topic><topic>Cell-Free Nucleic Acids - cerebrospinal fluid</topic><topic>cerebrospinal fluid</topic><topic>cfDNA</topic><topic>DNA Copy Number Variations</topic><topic>EGFR mutations</topic><topic>Female</topic><topic>Gene Expression Profiling</topic><topic>Genes, erbB-1</topic><topic>Genes, p53</topic><topic>Humans</topic><topic>leptomeningeal metastases</topic><topic>liquid biopsy</topic><topic>Liquid Biopsy - methods</topic><topic>Loss of Heterozygosity</topic><topic>Lung Neoplasms - cerebrospinal fluid</topic><topic>Lung Neoplasms - genetics</topic><topic>Lung Neoplasms - pathology</topic><topic>Male</topic><topic>Meningeal Neoplasms - cerebrospinal fluid</topic><topic>Meningeal Neoplasms - pathology</topic><topic>Meningeal Neoplasms - secondary</topic><topic>Middle Aged</topic><topic>Mutation</topic><topic>non-small-cell lung cancer</topic><topic>Spinal Puncture</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Li, Y.S.</creatorcontrib><creatorcontrib>Jiang, B.Y.</creatorcontrib><creatorcontrib>Yang, J.J.</creatorcontrib><creatorcontrib>Zhang, X.C.</creatorcontrib><creatorcontrib>Zhang, Z.</creatorcontrib><creatorcontrib>Ye, J.Y.</creatorcontrib><creatorcontrib>Zhong, W.Z.</creatorcontrib><creatorcontrib>Tu, H.Y.</creatorcontrib><creatorcontrib>Chen, H.J.</creatorcontrib><creatorcontrib>Wang, Z.</creatorcontrib><creatorcontrib>Xu, C.R.</creatorcontrib><creatorcontrib>Wang, B.C.</creatorcontrib><creatorcontrib>Du, H.J.</creatorcontrib><creatorcontrib>Chuai, S.</creatorcontrib><creatorcontrib>Han-Zhang, H.</creatorcontrib><creatorcontrib>Su, J.</creatorcontrib><creatorcontrib>Zhou, Q.</creatorcontrib><creatorcontrib>Yang, X.N.</creatorcontrib><creatorcontrib>Guo, W.B.</creatorcontrib><creatorcontrib>Yan, H.H.</creatorcontrib><creatorcontrib>Liu, Y.H.</creatorcontrib><creatorcontrib>Yan, L.X.</creatorcontrib><creatorcontrib>Huang, B.</creatorcontrib><creatorcontrib>Zheng, M.M.</creatorcontrib><creatorcontrib>Wu, Y.L.</creatorcontrib><collection>ScienceDirect Open Access Titles</collection><collection>Elsevier:ScienceDirect:Open Access</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>Annals of oncology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Li, Y.S.</au><au>Jiang, B.Y.</au><au>Yang, J.J.</au><au>Zhang, X.C.</au><au>Zhang, Z.</au><au>Ye, J.Y.</au><au>Zhong, W.Z.</au><au>Tu, H.Y.</au><au>Chen, H.J.</au><au>Wang, Z.</au><au>Xu, C.R.</au><au>Wang, B.C.</au><au>Du, H.J.</au><au>Chuai, S.</au><au>Han-Zhang, H.</au><au>Su, J.</au><au>Zhou, Q.</au><au>Yang, X.N.</au><au>Guo, W.B.</au><au>Yan, H.H.</au><au>Liu, Y.H.</au><au>Yan, L.X.</au><au>Huang, B.</au><au>Zheng, M.M.</au><au>Wu, Y.L.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Unique genetic profiles from cerebrospinal fluid cell-free DNA in leptomeningeal metastases of EGFR-mutant non-small-cell lung cancer: a new medium of liquid biopsy</atitle><jtitle>Annals of oncology</jtitle><addtitle>Ann Oncol</addtitle><date>2018-04</date><risdate>2018</risdate><volume>29</volume><issue>4</issue><spage>945</spage><epage>952</epage><pages>945-952</pages><issn>0923-7534</issn><eissn>1569-8041</eissn><abstract>Leptomeningeal metastases (LM) are more frequent in non-small-cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) mutations. Due to limited access to leptomeningeal lesions, the purpose of this study was to explore the potential role of cerebrospinal fluid (CSF) as a source of liquid biopsy in patients with LM.
Primary tumor, CSF, and plasma in NSCLC with LM were tested by next-generation sequencing. In total, 45 patients with suspected LM underwent lumbar puncture, and those with EGFR mutations diagnosed with LM were enrolled.
A total of 28 patients were enrolled in this cohort; CSF and plasma were available in 26 patients, respectively. Driver genes were detected in 100% (26/26), 84.6% (22/26), and 73.1% (19/26) of samples comprising CSF cell-free DNA (cfDNA), CSF precipitates, and plasma, respectively; 92.3% (24/26) of patients had much higher allele fractions in CSF cfDNA than the other two media. Unique genetic profiles were captured in CSF cfDNA compared with those in plasma and primary tissue. Multiple copy number variations (CNVs) were mainly identified in CSF cfDNA, and MET copy number gain identified in 47.8% (11/23) of patients was the most frequent one, while other CNVs included ERBB2, KRAS, ALK, and MYC. Moreover, loss of heterozygosity (LOH) of TP53 was identified in 73.1% (19/26) CSF cfDNA, which was much higher than that in plasma (2/26, 7.7%; P<0.001). There was a trend towards a higher frequency of concomitant resistance mutations in patients with TP53 LOH than those without (70.6% versus 33.3%; P=0.162). EGFR T790M was identified in CSF cfDNA of 30.4% (7/23) of patients who experienced TKI progression.
CSF cfDNA could reveal the unique genetic profiles of LM and should be considered as the most representative liquid biopsy medium for LM in EGFR-mutant NSCLC.</abstract><cop>England</cop><pub>Elsevier Ltd</pub><pmid>29346604</pmid><doi>10.1093/annonc/mdy009</doi><tpages>8</tpages><oa>free_for_read</oa></addata></record> |
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| ispartof | Annals of oncology, 2018-04, Vol.29 (4), p.945-952 |
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| subjects | Adult Aged Aged, 80 and over Carcinoma, Non-Small-Cell Lung - cerebrospinal fluid Carcinoma, Non-Small-Cell Lung - genetics Carcinoma, Non-Small-Cell Lung - pathology Cell-Free Nucleic Acids - cerebrospinal fluid cerebrospinal fluid cfDNA DNA Copy Number Variations EGFR mutations Female Gene Expression Profiling Genes, erbB-1 Genes, p53 Humans leptomeningeal metastases liquid biopsy Liquid Biopsy - methods Loss of Heterozygosity Lung Neoplasms - cerebrospinal fluid Lung Neoplasms - genetics Lung Neoplasms - pathology Male Meningeal Neoplasms - cerebrospinal fluid Meningeal Neoplasms - pathology Meningeal Neoplasms - secondary Middle Aged Mutation non-small-cell lung cancer Spinal Puncture |
| title | Unique genetic profiles from cerebrospinal fluid cell-free DNA in leptomeningeal metastases of EGFR-mutant non-small-cell lung cancer: a new medium of liquid biopsy |
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