NAB2::STAT6 fusions and genome-wide DNA methylation profiling: Predictors of patient outcomes in meningeal solitary fibrous tumors

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

NAB2::STAT6 fusions and genome-wide DNA methylation profiling: Predictors of patient outcomes in meningeal solitary fibrous tumors

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. RaleighMinh P. Nguyen, John Gross, Jose Velazquez Vega, Fausto Rodriguez, Arie Perry, Maria Martinez-Lage, Brent A. Orr, Florian Haller, Caterina Giannini^*

^*Corresponding author for this work

Pathology

Research output: Contribution to journal › Article › peer-review

Abstract

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.

Original language	English (US)
Journal	Brain Pathology
DOIs	https://doi.org/10.1111/bpa.13256
State	Accepted/In press - 2024

Keywords

CNS WHO grade
meningeal solitary fibrous tumor
NAB2::STAT6
solitary fibrous tumor
TERT

ASJC Scopus subject areas

General Neuroscience
Pathology and Forensic Medicine
Clinical Neurology

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10.1111/bpa.13256

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Eschbacher, K. L., Tran, Q. T., Moskalev, E. A., Jenkins, S., Fritchie, K., Stoehr, R., Caron, A., Link, M. J., Brown, P. D., Guajardo, A., Brat, D. J., Wu, A., Santagata, S., Louis, D. N., Brastianos, P. K., Kaplan, A. B., Alexander, B., Rossi, S., Ferrarese, F., ... Giannini, C. (Accepted/In press). NAB2::STAT6 fusions and genome-wide DNA methylation profiling: Predictors of patient outcomes in meningeal solitary fibrous tumors. Brain Pathology. https://doi.org/10.1111/bpa.13256

@article{1e7c97b7025348baab66b337523114ee,

title = "NAB2::STAT6 fusions and genome-wide DNA methylation profiling: Predictors of patient outcomes in meningeal solitary fibrous tumors",

abstract = "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.",

keywords = "CNS WHO grade, meningeal solitary fibrous tumor, NAB2::STAT6, solitary fibrous tumor, TERT",

author = "Eschbacher, {Kathryn L.} and Tran, {Quynh T.} and Moskalev, {Evgeny A.} and Sarah Jenkins and Karen Fritchie and Robert Stoehr and Alissa Caron and Link, {Michael J.} and Brown, {Paul D.} and Andrew Guajardo and Brat, {Daniel J.} and Ashley Wu and Sandro Santagata and Louis, {David N.} and Brastianos, {Priscilla K.} and Kaplan, {Alexander B.} and Brian Alexander and Sabrina Rossi and Fabio Ferrarese and Raleigh, {David R.} and Nguyen, {Minh P.} and John Gross and {Velazquez Vega}, Jose and Fausto Rodriguez and Arie Perry and Maria Martinez-Lage and Orr, {Brent A.} and Florian Haller and Caterina Giannini",

note = "Publisher Copyright: {\textcopyright} 2024 The Authors. Brain Pathology published by John Wiley & Sons Ltd on behalf of International Society of Neuropathology.",

year = "2024",

doi = "10.1111/bpa.13256",

language = "English (US)",

journal = "Brain Pathology",

issn = "1015-6305",

publisher = "Wiley-Blackwell",

}

Eschbacher, KL, Tran, QT, Moskalev, EA, Jenkins, S, Fritchie, K, Stoehr, R, Caron, A, Link, MJ, Brown, PD, Guajardo, A, Brat, DJ, Wu, A, Santagata, S, Louis, DN, Brastianos, PK, Kaplan, AB, Alexander, B, Rossi, S, Ferrarese, F, Raleigh, DR, Nguyen, MP, Gross, J, Velazquez Vega, J, Rodriguez, F, Perry, A, Martinez-Lage, M, Orr, BA, Haller, F & Giannini, C 2024, 'NAB2::STAT6 fusions and genome-wide DNA methylation profiling: Predictors of patient outcomes in meningeal solitary fibrous tumors', Brain Pathology. https://doi.org/10.1111/bpa.13256

TY - JOUR

T1 - NAB2::STAT6 fusions and genome-wide DNA methylation profiling: Predictors of patient outcomes in meningeal solitary fibrous tumors

AU - Eschbacher, Kathryn L.

AU - Tran, Quynh T.

AU - Moskalev, Evgeny A.

AU - Jenkins, Sarah

AU - Fritchie, Karen

AU - Stoehr, Robert

AU - Caron, Alissa

AU - Link, Michael J.

AU - Brown, Paul D.

AU - Guajardo, Andrew

AU - Brat, Daniel J.

AU - Wu, Ashley

AU - Santagata, Sandro

AU - Louis, David N.

AU - Brastianos, Priscilla K.

AU - Kaplan, Alexander B.

AU - Alexander, Brian

AU - Rossi, Sabrina

AU - Ferrarese, Fabio

AU - Raleigh, David R.

AU - Nguyen, Minh P.

AU - Gross, John

AU - Velazquez Vega, Jose

AU - Rodriguez, Fausto

AU - Perry, Arie

AU - Martinez-Lage, Maria

AU - Orr, Brent A.

AU - Haller, Florian

AU - Giannini, Caterina

PY - 2024

Y1 - 2024

N2 - 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.

AB - 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.

KW - CNS WHO grade

KW - meningeal solitary fibrous tumor

KW - NAB2::STAT6

KW - solitary fibrous tumor

KW - TERT

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U2 - 10.1111/bpa.13256

DO - 10.1111/bpa.13256

M3 - Article

C2 - 38523251

AN - SCOPUS:85189537482

SN - 1015-6305

JO - Brain Pathology

JF - Brain Pathology

ER -

NAB2::STAT6 fusions and genome-wide DNA methylation profiling: Predictors of patient outcomes in meningeal solitary fibrous tumors

Abstract

Keywords

ASJC Scopus subject areas

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