Plasma DNA Methylation‐Based Biomarkers for MPNST Detection in Patients With Neurofibromatosis Type 1
ABSTRACT Malignant peripheral nerve sheath tumor (MPNST) development is characterized by an altered DNA methylation landscape, which presents a promising area for developing MPNST‐specific biomarkers for screening patients with NF1. Genome‐wide DNA methylation profiling of a cohort of 13 patients wi...
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| Veröffentlicht in: | Molecular carcinogenesis 2024-11, Vol.64 (1), p.44-56 |
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| creator | Tomczak, Katarzyna Patel, Manishkumar S. Bhalla, Angela D. Peterson, Christine B. Landers, Sharon M. Callahan, S. Carson Zhang, Di Wong, Justin Landry, Jace P. Lazar, Alexander J. Livingston, J. Andrew Guadagnolo, B. Ashleigh Lyu, Heather G. Lillemoe, Heather Roland, Christina L. Keung, Emily Z. Scally, Christopher P. Hunt, Kelly K. McCutcheon, Ian E. Slopis, John M. Gu, Jian Scheet, Paul Wang, Liang Rai, Kunal Torres, Keila E. |
| description | ABSTRACT
Malignant peripheral nerve sheath tumor (MPNST) development is characterized by an altered DNA methylation landscape, which presents a promising area for developing MPNST‐specific biomarkers for screening patients with NF1. Genome‐wide DNA methylation profiling of a cohort of 13 patients with MPNST (29 samples of tumor and adjacent neurofibroma tissues) and of NF1‐MPNST cell lines was performed to identify and validate candidate MPNST‐specific CpG sites (CpGs). A logistic regression prediction model was constructed to select MPNST‐specific CpGs distinct from adjacent neurofibromas and normal tissues. To test if hypermethylation at selected CpGs can also be detected in plasma from patients with MPNST, cfMBD‐seq was applied to profile the cfDNA methylome of blood from patients with MPNST and NF1. Based on stringent feature‐selection criteria and predictive modeling, we identified 73 candidate MPNST‐specific CpGs (67 with unique CpG island locations) that reliably discriminated MPNSTs from neurofibromas. Validation of five candidate biomarkers confirmed successful MPNST detection (sensitivity: > 88%, specificity: > 91%) in tissues. In plasma samples, 63 of 67 selected genomic regions had greater than 1.2‐fold higher methylation in patients with MPNST than those with NF1. Further, we identified 15 CpG islands that consistently separated plasma from patients with confirmed MPNST diagnosis from plasma of individuals with NF1 without a diagnosis of malignant transformation (FDR |
| doi_str_mv | 10.1002/mc.23825 |
| format | Article |
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Malignant peripheral nerve sheath tumor (MPNST) development is characterized by an altered DNA methylation landscape, which presents a promising area for developing MPNST‐specific biomarkers for screening patients with NF1. Genome‐wide DNA methylation profiling of a cohort of 13 patients with MPNST (29 samples of tumor and adjacent neurofibroma tissues) and of NF1‐MPNST cell lines was performed to identify and validate candidate MPNST‐specific CpG sites (CpGs). A logistic regression prediction model was constructed to select MPNST‐specific CpGs distinct from adjacent neurofibromas and normal tissues. To test if hypermethylation at selected CpGs can also be detected in plasma from patients with MPNST, cfMBD‐seq was applied to profile the cfDNA methylome of blood from patients with MPNST and NF1. Based on stringent feature‐selection criteria and predictive modeling, we identified 73 candidate MPNST‐specific CpGs (67 with unique CpG island locations) that reliably discriminated MPNSTs from neurofibromas. Validation of five candidate biomarkers confirmed successful MPNST detection (sensitivity: > 88%, specificity: > 91%) in tissues. In plasma samples, 63 of 67 selected genomic regions had greater than 1.2‐fold higher methylation in patients with MPNST than those with NF1. Further, we identified 15 CpG islands that consistently separated plasma from patients with confirmed MPNST diagnosis from plasma of individuals with NF1 without a diagnosis of malignant transformation (FDR < 0.1). Our findings confirmed a unique hypermethylation pattern present during malignant transformation. This study highlights the potential to be investigated further as biomarkers in clinical settings for early MPNST detection in patients with NF1.</description><identifier>ISSN: 0899-1987</identifier><identifier>ISSN: 1098-2744</identifier><identifier>EISSN: 1098-2744</identifier><identifier>DOI: 10.1002/mc.23825</identifier><identifier>PMID: 39600120</identifier><language>eng</language><publisher>United States: Wiley Subscription Services, Inc</publisher><subject>Adult ; Aged ; biomarker ; Biomarkers ; Biomarkers, Tumor - blood ; Biomarkers, Tumor - genetics ; Cell Line, Tumor ; CpG Islands ; Diagnosis ; DNA fingerprinting ; DNA Methylation ; Female ; Genetic transformation ; Humans ; Male ; Middle Aged ; MPNST ; Neurofibromatosis ; Neurofibromatosis 1 - blood ; Neurofibromatosis 1 - diagnosis ; Neurofibromatosis 1 - genetics ; neurofibromatosis type 1 ; Neurofibrosarcoma - blood ; Neurofibrosarcoma - diagnosis ; Neurofibrosarcoma - genetics ; Peripheral nerves ; Plasma ; Prediction models ; Recklinghausen's disease ; Tumor cell lines ; Tumors</subject><ispartof>Molecular carcinogenesis, 2024-11, Vol.64 (1), p.44-56</ispartof><rights>2024 The Author(s). published by Wiley Periodicals LLC.</rights><rights>2024 The Author(s). Molecular Carcinogenesis published by Wiley Periodicals LLC.</rights><rights>2024. This article is published under http://creativecommons.org/licenses/by-nc/4.0/ (the “License”). 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Carson</creatorcontrib><creatorcontrib>Zhang, Di</creatorcontrib><creatorcontrib>Wong, Justin</creatorcontrib><creatorcontrib>Landry, Jace P.</creatorcontrib><creatorcontrib>Lazar, Alexander J.</creatorcontrib><creatorcontrib>Livingston, J. Andrew</creatorcontrib><creatorcontrib>Guadagnolo, B. Ashleigh</creatorcontrib><creatorcontrib>Lyu, Heather G.</creatorcontrib><creatorcontrib>Lillemoe, Heather</creatorcontrib><creatorcontrib>Roland, Christina L.</creatorcontrib><creatorcontrib>Keung, Emily Z.</creatorcontrib><creatorcontrib>Scally, Christopher P.</creatorcontrib><creatorcontrib>Hunt, Kelly K.</creatorcontrib><creatorcontrib>McCutcheon, Ian E.</creatorcontrib><creatorcontrib>Slopis, John M.</creatorcontrib><creatorcontrib>Gu, Jian</creatorcontrib><creatorcontrib>Scheet, Paul</creatorcontrib><creatorcontrib>Wang, Liang</creatorcontrib><creatorcontrib>Rai, Kunal</creatorcontrib><creatorcontrib>Torres, Keila E.</creatorcontrib><title>Plasma DNA Methylation‐Based Biomarkers for MPNST Detection in Patients With Neurofibromatosis Type 1</title><title>Molecular carcinogenesis</title><addtitle>Mol Carcinog</addtitle><description>ABSTRACT
Malignant peripheral nerve sheath tumor (MPNST) development is characterized by an altered DNA methylation landscape, which presents a promising area for developing MPNST‐specific biomarkers for screening patients with NF1. Genome‐wide DNA methylation profiling of a cohort of 13 patients with MPNST (29 samples of tumor and adjacent neurofibroma tissues) and of NF1‐MPNST cell lines was performed to identify and validate candidate MPNST‐specific CpG sites (CpGs). A logistic regression prediction model was constructed to select MPNST‐specific CpGs distinct from adjacent neurofibromas and normal tissues. To test if hypermethylation at selected CpGs can also be detected in plasma from patients with MPNST, cfMBD‐seq was applied to profile the cfDNA methylome of blood from patients with MPNST and NF1. Based on stringent feature‐selection criteria and predictive modeling, we identified 73 candidate MPNST‐specific CpGs (67 with unique CpG island locations) that reliably discriminated MPNSTs from neurofibromas. Validation of five candidate biomarkers confirmed successful MPNST detection (sensitivity: > 88%, specificity: > 91%) in tissues. In plasma samples, 63 of 67 selected genomic regions had greater than 1.2‐fold higher methylation in patients with MPNST than those with NF1. Further, we identified 15 CpG islands that consistently separated plasma from patients with confirmed MPNST diagnosis from plasma of individuals with NF1 without a diagnosis of malignant transformation (FDR < 0.1). Our findings confirmed a unique hypermethylation pattern present during malignant transformation. This study highlights the potential to be investigated further as biomarkers in clinical settings for early MPNST detection in patients with NF1.</description><subject>Adult</subject><subject>Aged</subject><subject>biomarker</subject><subject>Biomarkers</subject><subject>Biomarkers, Tumor - blood</subject><subject>Biomarkers, Tumor - genetics</subject><subject>Cell Line, Tumor</subject><subject>CpG Islands</subject><subject>Diagnosis</subject><subject>DNA fingerprinting</subject><subject>DNA Methylation</subject><subject>Female</subject><subject>Genetic transformation</subject><subject>Humans</subject><subject>Male</subject><subject>Middle Aged</subject><subject>MPNST</subject><subject>Neurofibromatosis</subject><subject>Neurofibromatosis 1 - blood</subject><subject>Neurofibromatosis 1 - diagnosis</subject><subject>Neurofibromatosis 1 - genetics</subject><subject>neurofibromatosis type 1</subject><subject>Neurofibrosarcoma - blood</subject><subject>Neurofibrosarcoma - diagnosis</subject><subject>Neurofibrosarcoma - genetics</subject><subject>Peripheral nerves</subject><subject>Plasma</subject><subject>Prediction models</subject><subject>Recklinghausen's disease</subject><subject>Tumor cell lines</subject><subject>Tumors</subject><issn>0899-1987</issn><issn>1098-2744</issn><issn>1098-2744</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2024</creationdate><recordtype>article</recordtype><sourceid>24P</sourceid><sourceid>WIN</sourceid><sourceid>EIF</sourceid><recordid>eNp1kctuEzEUhi1ERdOCxBMgS2zYTPFt7PEKtWkLSE2IRBBLy-OcaVxmxqk9Q5Udj8Az8iS4TSkXiY0ty9_5zjn6EXpOyRElhL3u3BHjFSsfoQkluiqYEuIxmpBK64LqSu2jg5SuCKFUleQJ2uda5gcjE3S5aG3qLD6dH-MZDOttawcf-h_fvp_YBCt84kNn4xeICTch4tli_nGJT2EAd4th3-NFLoB-SPizH9Z4DmMMja9jLhtC8gkvtxvA9Cnaa2yb4Nn9fYg-nZ8tp--Kiw9v30-PLwrHOSmLlXZWWtWUpG7UqtZWOEUUKCWUFLYU0jVMK7A1F6zUDAgDqQiVZZVPQTk_RG923s1Yd7ByebJoW7OJPq-xNcF68_dP79fmMnw1lEqeNTIbXt0bYrgeIQ2m88lB29oewpgMz12EJLqsMvryH_QqjLHP-2VKcCakoPq30MWQUoTmYRpKzG18pnPmLr6Mvvhz-gfwV14ZKHbAjW9h-1-RmU13wp-tYqML</recordid><startdate>20241126</startdate><enddate>20241126</enddate><creator>Tomczak, Katarzyna</creator><creator>Patel, Manishkumar S.</creator><creator>Bhalla, Angela D.</creator><creator>Peterson, Christine B.</creator><creator>Landers, Sharon M.</creator><creator>Callahan, S. 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Carson ; Zhang, Di ; Wong, Justin ; Landry, Jace P. ; Lazar, Alexander J. ; Livingston, J. Andrew ; Guadagnolo, B. 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Ashleigh</creatorcontrib><creatorcontrib>Lyu, Heather G.</creatorcontrib><creatorcontrib>Lillemoe, Heather</creatorcontrib><creatorcontrib>Roland, Christina L.</creatorcontrib><creatorcontrib>Keung, Emily Z.</creatorcontrib><creatorcontrib>Scally, Christopher P.</creatorcontrib><creatorcontrib>Hunt, Kelly K.</creatorcontrib><creatorcontrib>McCutcheon, Ian E.</creatorcontrib><creatorcontrib>Slopis, John M.</creatorcontrib><creatorcontrib>Gu, Jian</creatorcontrib><creatorcontrib>Scheet, Paul</creatorcontrib><creatorcontrib>Wang, Liang</creatorcontrib><creatorcontrib>Rai, Kunal</creatorcontrib><creatorcontrib>Torres, Keila E.</creatorcontrib><collection>Wiley Online Library (Open Access Collection)</collection><collection>Wiley Online Library Free Content</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Nucleic Acids Abstracts</collection><collection>Oncogenes and Growth Factors Abstracts</collection><collection>Technology Research Database</collection><collection>Engineering Research Database</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Genetics Abstracts</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Molecular carcinogenesis</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Tomczak, Katarzyna</au><au>Patel, Manishkumar S.</au><au>Bhalla, Angela D.</au><au>Peterson, Christine B.</au><au>Landers, Sharon M.</au><au>Callahan, S. Carson</au><au>Zhang, Di</au><au>Wong, Justin</au><au>Landry, Jace P.</au><au>Lazar, Alexander J.</au><au>Livingston, J. Andrew</au><au>Guadagnolo, B. Ashleigh</au><au>Lyu, Heather G.</au><au>Lillemoe, Heather</au><au>Roland, Christina L.</au><au>Keung, Emily Z.</au><au>Scally, Christopher P.</au><au>Hunt, Kelly K.</au><au>McCutcheon, Ian E.</au><au>Slopis, John M.</au><au>Gu, Jian</au><au>Scheet, Paul</au><au>Wang, Liang</au><au>Rai, Kunal</au><au>Torres, Keila E.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Plasma DNA Methylation‐Based Biomarkers for MPNST Detection in Patients With Neurofibromatosis Type 1</atitle><jtitle>Molecular carcinogenesis</jtitle><addtitle>Mol Carcinog</addtitle><date>2024-11-26</date><risdate>2024</risdate><volume>64</volume><issue>1</issue><spage>44</spage><epage>56</epage><pages>44-56</pages><issn>0899-1987</issn><issn>1098-2744</issn><eissn>1098-2744</eissn><abstract>ABSTRACT
Malignant peripheral nerve sheath tumor (MPNST) development is characterized by an altered DNA methylation landscape, which presents a promising area for developing MPNST‐specific biomarkers for screening patients with NF1. Genome‐wide DNA methylation profiling of a cohort of 13 patients with MPNST (29 samples of tumor and adjacent neurofibroma tissues) and of NF1‐MPNST cell lines was performed to identify and validate candidate MPNST‐specific CpG sites (CpGs). A logistic regression prediction model was constructed to select MPNST‐specific CpGs distinct from adjacent neurofibromas and normal tissues. To test if hypermethylation at selected CpGs can also be detected in plasma from patients with MPNST, cfMBD‐seq was applied to profile the cfDNA methylome of blood from patients with MPNST and NF1. Based on stringent feature‐selection criteria and predictive modeling, we identified 73 candidate MPNST‐specific CpGs (67 with unique CpG island locations) that reliably discriminated MPNSTs from neurofibromas. Validation of five candidate biomarkers confirmed successful MPNST detection (sensitivity: > 88%, specificity: > 91%) in tissues. In plasma samples, 63 of 67 selected genomic regions had greater than 1.2‐fold higher methylation in patients with MPNST than those with NF1. Further, we identified 15 CpG islands that consistently separated plasma from patients with confirmed MPNST diagnosis from plasma of individuals with NF1 without a diagnosis of malignant transformation (FDR < 0.1). Our findings confirmed a unique hypermethylation pattern present during malignant transformation. This study highlights the potential to be investigated further as biomarkers in clinical settings for early MPNST detection in patients with NF1.</abstract><cop>United States</cop><pub>Wiley Subscription Services, Inc</pub><pmid>39600120</pmid><doi>10.1002/mc.23825</doi><tpages>13</tpages><orcidid>https://orcid.org/0000-0003-2321-6894</orcidid><orcidid>https://orcid.org/0000-0002-0152-2666</orcidid><orcidid>https://orcid.org/0000-0002-1638-3400</orcidid><orcidid>https://orcid.org/0000-0001-7119-7005</orcidid><orcidid>https://orcid.org/0000-0003-3316-0468</orcidid><orcidid>https://orcid.org/0000-0002-6395-4499</orcidid><orcidid>https://orcid.org/0000-0002-1847-0583</orcidid><orcidid>https://orcid.org/0000-0001-9156-8723</orcidid><orcidid>https://orcid.org/0000-0001-7759-0799</orcidid><orcidid>https://orcid.org/0000-0003-3499-0973</orcidid><orcidid>https://orcid.org/0000-0002-4489-7070</orcidid><orcidid>https://orcid.org/0000-0001-9044-5510</orcidid><orcidid>https://orcid.org/0000-0002-1337-3282</orcidid><orcidid>https://orcid.org/0000-0003-3400-0087</orcidid><orcidid>https://orcid.org/0000-0002-9364-8572</orcidid><orcidid>https://orcid.org/0000-0001-8863-1066</orcidid><orcidid>https://orcid.org/0000-0002-1855-0989</orcidid><orcidid>https://orcid.org/0000-0002-6803-1060</orcidid><orcidid>https://orcid.org/0000-0002-8783-8484</orcidid><orcidid>https://orcid.org/0000-0002-2450-0662</orcidid><orcidid>https://orcid.org/0000-0002-5173-7497</orcidid><orcidid>https://orcid.org/0000-0002-8732-7764</orcidid><orcidid>https://orcid.org/0000-0003-0553-8056</orcidid><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0899-1987 |
| ispartof | Molecular carcinogenesis, 2024-11, Vol.64 (1), p.44-56 |
| issn | 0899-1987 1098-2744 1098-2744 |
| language | eng |
| recordid | cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_11636586 |
| source | Wiley Online Library - AutoHoldings Journals; MEDLINE |
| subjects | Adult Aged biomarker Biomarkers Biomarkers, Tumor - blood Biomarkers, Tumor - genetics Cell Line, Tumor CpG Islands Diagnosis DNA fingerprinting DNA Methylation Female Genetic transformation Humans Male Middle Aged MPNST Neurofibromatosis Neurofibromatosis 1 - blood Neurofibromatosis 1 - diagnosis Neurofibromatosis 1 - genetics neurofibromatosis type 1 Neurofibrosarcoma - blood Neurofibrosarcoma - diagnosis Neurofibrosarcoma - genetics Peripheral nerves Plasma Prediction models Recklinghausen's disease Tumor cell lines Tumors |
| title | Plasma DNA Methylation‐Based Biomarkers for MPNST Detection in Patients With Neurofibromatosis Type 1 |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2024-12-20T08%3A34%3A31IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_pubme&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Plasma%20DNA%20Methylation%E2%80%90Based%20Biomarkers%20for%20MPNST%20Detection%20in%20Patients%20With%20Neurofibromatosis%20Type%201&rft.jtitle=Molecular%20carcinogenesis&rft.au=Tomczak,%20Katarzyna&rft.date=2024-11-26&rft.volume=64&rft.issue=1&rft.spage=44&rft.epage=56&rft.pages=44-56&rft.issn=0899-1987&rft.eissn=1098-2744&rft_id=info:doi/10.1002/mc.23825&rft_dat=%3Cproquest_pubme%3E3133460958%3C/proquest_pubme%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=3143246419&rft_id=info:pmid/39600120&rfr_iscdi=true |