Kathryn L. Eschbacher, Quynh T. Tran, Evgeny A. Moskalev, Sarah Jenkins, Karen Fritchie, Robert Stoehr, Alissa Caron, Michael J. Link, Paul D. Brown, Andrew Guajardo, Daniel J. Brat, Ashley Wu, Sandro Santagata, David N. Louis, Priscilla K. Brastianos, Alexander B. Kaplan, Brian Alexander, Sabrina Rossi, Fabio Ferrarese, David R. Raleigh, Minh P. Nguyen, John Gross, Jose Velazquez Vega, Fausto Rodriguez, Arie Perry, Maria Martinez-Lage, Brent A. Orr, Florian Haller, Caterina Giannini
{"title":"NAB2::STAT6融合和全基因组DNA甲基化分析：脑膜单发纤维瘤患者预后的预测因素。","authors":"Kathryn L. Eschbacher, Quynh T. Tran, Evgeny A. Moskalev, Sarah Jenkins, Karen Fritchie, Robert Stoehr, Alissa Caron, Michael J. Link, Paul D. Brown, Andrew Guajardo, Daniel J. Brat, Ashley Wu, Sandro Santagata, David N. Louis, Priscilla K. Brastianos, Alexander B. Kaplan, Brian Alexander, Sabrina Rossi, Fabio Ferrarese, David R. Raleigh, Minh P. Nguyen, John Gross, Jose Velazquez Vega, Fausto Rodriguez, Arie Perry, Maria Martinez-Lage, Brent A. Orr, Florian Haller, Caterina Giannini","doi":"10.1111/bpa.13256","DOIUrl":null,"url":null,"abstract":"<p>Meningeal solitary fibrous tumors (SFT) are rare and have a high frequency of local recurrence and distant metastasis. In a cohort of 126 patients (57 female, 69 male; mean age at surgery 53.0 years) with pathologically confirmed meningeal SFTs with extended clinical follow-up (median 9.9 years; range 15 days–43 years), we performed extensive molecular characterization including genome-wide DNA methylation profiling (<i>n</i> = 80) and targeted <i>TERT</i> promoter mutation testing (<i>n</i> = 98). Associations were examined with <i>NAB2::STAT6</i> fusion status (<i>n</i> = 101 cases; 51 = ex5-7::ex16-17, 26 = ex4::ex2-3; 12 = ex2-3::exANY/other and 12 = no fusion) and placed in the context of 2021 Central Nervous System (CNS) WHO grade. <i>NAB2::STAT6</i> fusion breakpoints (fusion type) were significantly associated with metastasis-free survival (MFS) (<i>p</i> = 0.03) and, on multivariate analysis, disease-specific survival (DSS) when adjusting for CNS WHO grade (<i>p</i> = 0.03). DNA methylation profiling revealed three distinct clusters: Cluster 1 (<i>n</i> = 38), Cluster 2 (<i>n</i> = 22), and Cluster 3 (<i>n</i> = 20). Methylation clusters were significantly associated with fusion type (<i>p</i> < 0.001), with Cluster 2 harboring ex4::ex2-3 fusion in 16 (of 20; 80.0%), nearly all <i>TERT</i> promoter mutations (7 of 8; 87.5%), and predominantly an “SFT” histologic phenotype (15 of 22; 68.2%). Clusters 1 and 3 were less distinct, both dominated by tumors having ex5-7::ex16-17 fusion (respectively, 25 of 33; 75.8%, and 12 of 18; 66.7%) and with variable histological phenotypes. Methylation clusters were significantly associated with MFS (<i>p</i> = 0.027), but not overall survival (OS). In summary, <i>NAB2::STAT6</i> fusion type was significantly associated with MFS and DSS, suggesting that tumors with an ex5::ex16-17 fusion may have inferior patient outcomes. Methylation clusters were significantly associated with fusion type, <i>TERT</i> promoter mutation status, histologic phenotype, and MFS.</p>","PeriodicalId":9290,"journal":{"name":"Brain Pathology","volume":"34 6","pages":""},"PeriodicalIF":5.8000,"publicationDate":"2024-03-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/bpa.13256","citationCount":"0","resultStr":"{\"title\":\"NAB2::STAT6 fusions and genome-wide DNA methylation profiling: Predictors of patient outcomes in meningeal solitary fibrous tumors\",\"authors\":\"Kathryn L. Eschbacher, Quynh T. Tran, Evgeny A. Moskalev, Sarah Jenkins, Karen Fritchie, Robert Stoehr, Alissa Caron, Michael J. Link, Paul D. Brown, Andrew Guajardo, Daniel J. Brat, Ashley Wu, Sandro Santagata, David N. Louis, Priscilla K. Brastianos, Alexander B. Kaplan, Brian Alexander, Sabrina Rossi, Fabio Ferrarese, David R. Raleigh, Minh P. Nguyen, John Gross, Jose Velazquez Vega, Fausto Rodriguez, Arie Perry, Maria Martinez-Lage, Brent A. Orr, Florian Haller, Caterina Giannini\",\"doi\":\"10.1111/bpa.13256\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p>Meningeal solitary fibrous tumors (SFT) are rare and have a high frequency of local recurrence and distant metastasis. In a cohort of 126 patients (57 female, 69 male; mean age at surgery 53.0 years) with pathologically confirmed meningeal SFTs with extended clinical follow-up (median 9.9 years; range 15 days–43 years), we performed extensive molecular characterization including genome-wide DNA methylation profiling (<i>n</i> = 80) and targeted <i>TERT</i> promoter mutation testing (<i>n</i> = 98). Associations were examined with <i>NAB2::STAT6</i> fusion status (<i>n</i> = 101 cases; 51 = ex5-7::ex16-17, 26 = ex4::ex2-3; 12 = ex2-3::exANY/other and 12 = no fusion) and placed in the context of 2021 Central Nervous System (CNS) WHO grade. <i>NAB2::STAT6</i> fusion breakpoints (fusion type) were significantly associated with metastasis-free survival (MFS) (<i>p</i> = 0.03) and, on multivariate analysis, disease-specific survival (DSS) when adjusting for CNS WHO grade (<i>p</i> = 0.03). DNA methylation profiling revealed three distinct clusters: Cluster 1 (<i>n</i> = 38), Cluster 2 (<i>n</i> = 22), and Cluster 3 (<i>n</i> = 20). Methylation clusters were significantly associated with fusion type (<i>p</i> < 0.001), with Cluster 2 harboring ex4::ex2-3 fusion in 16 (of 20; 80.0%), nearly all <i>TERT</i> promoter mutations (7 of 8; 87.5%), and predominantly an “SFT” histologic phenotype (15 of 22; 68.2%). Clusters 1 and 3 were less distinct, both dominated by tumors having ex5-7::ex16-17 fusion (respectively, 25 of 33; 75.8%, and 12 of 18; 66.7%) and with variable histological phenotypes. Methylation clusters were significantly associated with MFS (<i>p</i> = 0.027), but not overall survival (OS). In summary, <i>NAB2::STAT6</i> fusion type was significantly associated with MFS and DSS, suggesting that tumors with an ex5::ex16-17 fusion may have inferior patient outcomes. Methylation clusters were significantly associated with fusion type, <i>TERT</i> promoter mutation status, histologic phenotype, and MFS.</p>\",\"PeriodicalId\":9290,\"journal\":{\"name\":\"Brain Pathology\",\"volume\":\"34 6\",\"pages\":\"\"},\"PeriodicalIF\":5.8000,\"publicationDate\":\"2024-03-24\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://onlinelibrary.wiley.com/doi/epdf/10.1111/bpa.13256\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Brain Pathology\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://onlinelibrary.wiley.com/doi/10.1111/bpa.13256\",\"RegionNum\":2,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"CLINICAL NEUROLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Brain Pathology","FirstCategoryId":"3","ListUrlMain":"https://onlinelibrary.wiley.com/doi/10.1111/bpa.13256","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"CLINICAL NEUROLOGY","Score":null,"Total":0}
NAB2::STAT6 fusions and genome-wide DNA methylation profiling: Predictors of patient outcomes in meningeal solitary fibrous tumors
Meningeal solitary fibrous tumors (SFT) are rare and have a high frequency of local recurrence and distant metastasis. In a cohort of 126 patients (57 female, 69 male; mean age at surgery 53.0 years) with pathologically confirmed meningeal SFTs with extended clinical follow-up (median 9.9 years; range 15 days–43 years), we performed extensive molecular characterization including genome-wide DNA methylation profiling (n = 80) and targeted TERT promoter mutation testing (n = 98). Associations were examined with NAB2::STAT6 fusion status (n = 101 cases; 51 = ex5-7::ex16-17, 26 = ex4::ex2-3; 12 = ex2-3::exANY/other and 12 = no fusion) and placed in the context of 2021 Central Nervous System (CNS) WHO grade. NAB2::STAT6 fusion breakpoints (fusion type) were significantly associated with metastasis-free survival (MFS) (p = 0.03) and, on multivariate analysis, disease-specific survival (DSS) when adjusting for CNS WHO grade (p = 0.03). DNA methylation profiling revealed three distinct clusters: Cluster 1 (n = 38), Cluster 2 (n = 22), and Cluster 3 (n = 20). Methylation clusters were significantly associated with fusion type (p < 0.001), with Cluster 2 harboring ex4::ex2-3 fusion in 16 (of 20; 80.0%), nearly all TERT promoter mutations (7 of 8; 87.5%), and predominantly an “SFT” histologic phenotype (15 of 22; 68.2%). Clusters 1 and 3 were less distinct, both dominated by tumors having ex5-7::ex16-17 fusion (respectively, 25 of 33; 75.8%, and 12 of 18; 66.7%) and with variable histological phenotypes. Methylation clusters were significantly associated with MFS (p = 0.027), but not overall survival (OS). In summary, NAB2::STAT6 fusion type was significantly associated with MFS and DSS, suggesting that tumors with an ex5::ex16-17 fusion may have inferior patient outcomes. Methylation clusters were significantly associated with fusion type, TERT promoter mutation status, histologic phenotype, and MFS.
期刊介绍：
Brain Pathology is the journal of choice for biomedical scientists investigating diseases of the nervous system. The official journal of the International Society of Neuropathology, Brain Pathology is a peer-reviewed quarterly publication that includes original research, review articles and symposia focuses on the pathogenesis of neurological disease.
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