Heterogeneity within the PF-EPN-B ependymoma subgroup

Florence M.G. Cavalli; Jens Martin Hübner; Tanvi Sharma; Betty Luu; Martin Sill; Michal Zapotocky; Stephen C. Mack; Hendrik Witt; Tong Lin; David J.H. Shih; Ben Ho; Mariarita Santi; Lyndsey Emery; Juliette Hukin; Christopher Dunham; Roger E. McLendon; Eric S. Lipp; Sridharan Gururangan; Andrew Grossbach; Pim French; Johan M. Kros; Marie Lise C. van Veelen; Amulya A.Nageswara Rao; Caterina Giannini; Sarah Leary; Shin Jung; Claudia C. Faria; Jaume Mora; Ulrich Schüller; Marta M. Alonso; Jennifer A. Chan; Almos Klekner; Lola B. Chambless; Eugene I. Hwang; Maura Massimino; Charles G. Eberhart; Matthias A. Karajannis; Benjamin Lu; Linda M. Liau; Massimo Zollo; Veronica Ferrucci; Carlos Carlotti; Daniela P.C. Tirapelli; Uri Tabori; Eric Bouffet; Marina Ryzhova; David W. Ellison; Thomas E. Merchant; Mark R. Gilbert; Terri S. Armstrong; Andrey Korshunov; Stefan M. Pfister; Michael D. Taylor; Kenneth Aldape; Kristian W. Pajtler; Marcel Kool; Vijay Ramaswamy

doi:10.1007/s00401-018-1888-x

Heterogeneity within the PF-EPN-B ependymoma subgroup

Florence M.G. Cavalli, Jens Martin Hübner, Tanvi Sharma, Betty Luu, Martin Sill, Michal Zapotocky, Stephen C. Mack, Hendrik Witt, Tong Lin, David J.H. Shih, Ben Ho, Mariarita Santi, Lyndsey Emery, Juliette Hukin, Christopher Dunham, Roger E. McLendon, Eric S. Lipp, Sridharan Gururangan, Andrew Grossbach, Pim FrenchJohan M. Kros, Marie Lise C. van Veelen, Amulya A.Nageswara Rao, Caterina Giannini, Sarah Leary, Shin Jung, Claudia C. Faria, Jaume Mora, Ulrich Schüller, Marta M. Alonso, Jennifer A. Chan, Almos Klekner, Lola B. Chambless, Eugene I. Hwang, Maura Massimino, Charles G. Eberhart, Matthias A. Karajannis, Benjamin Lu, Linda M. Liau, Massimo Zollo, Veronica Ferrucci, Carlos Carlotti, Daniela P.C. Tirapelli, Uri Tabori, Eric Bouffet, Marina Ryzhova, David W. Ellison, Thomas E. Merchant, Mark R. Gilbert, Terri S. Armstrong, Andrey Korshunov, Stefan M. Pfister, Michael D. Taylor, Kenneth Aldape, Kristian W. Pajtler, Marcel Kool, Vijay Ramaswamy

School of Medicine

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

Abstract

Posterior fossa ependymoma comprise three distinct molecular variants, termed PF-EPN-A (PFA), PF-EPN-B (PFB), and PF-EPN-SE (subependymoma). Clinically, they are very disparate and PFB tumors are currently being considered for a trial of radiation avoidance. However, to move forward, unraveling the heterogeneity within PFB would be highly desirable. To discern the molecular heterogeneity within PFB, we performed an integrated analysis consisting of DNA methylation profiling, copy-number profiling, gene expression profiling, and clinical correlation across a cohort of 212 primary posterior fossa PFB tumors. Unsupervised spectral clustering and t-SNE analysis of genome-wide methylation data revealed five distinct subtypes of PFB tumors, termed PFB1-5, with distinct demographics, copy-number alterations, and gene expression profiles. All PFB subtypes were distinct from PFA and posterior fossa subependymomas. Of the five subtypes, PFB4 and PFB5 are more discrete, consisting of younger and older patients, respectively, with a strong female-gender enrichment in PFB5 (age: p = 0.011, gender: p = 0.04). Broad copy-number aberrations were common; however, many events such as chromosome 2 loss, 5 gain, and 17 loss were enriched in specific subtypes and 1q gain was enriched in PFB1. Late relapses were common across all five subtypes, but deaths were uncommon and present in only two subtypes (PFB1 and PFB3). Unlike the case in PFA ependymoma, 1q gain was not a robust marker of poor progression-free survival; however, chromosome 13q loss may represent a novel marker for risk stratification across the spectrum of PFB subtypes. Similar to PFA ependymoma, there exists a significant intertumoral heterogeneity within PFB, with distinct molecular subtypes identified. Even when accounting for this heterogeneity, extent of resection remains the strongest predictor of poor outcome. However, this biological heterogeneity must be accounted for in future preclinical modeling and personalized therapies.

Original language	English (US)
Pages (from-to)	227-237
Number of pages	11
Journal	Acta neuropathologica
Volume	136
Issue number	2
DOIs	https://doi.org/10.1007/s00401-018-1888-x
State	Published - Aug 1 2018

Keywords

Clustering
Ependymoma
PFA
PFB
Posterior fossa
Subgrouping

ASJC Scopus subject areas

Pathology and Forensic Medicine
Clinical Neurology
Cellular and Molecular Neuroscience

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10.1007/s00401-018-1888-x

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Cavalli, F. M. G., Hübner, J. M., Sharma, T., Luu, B., Sill, M., Zapotocky, M., Mack, S. C., Witt, H., Lin, T., Shih, D. J. H., Ho, B., Santi, M., Emery, L., Hukin, J., Dunham, C., McLendon, R. E., Lipp, E. S., Gururangan, S., Grossbach, A., ... Ramaswamy, V. (2018). Heterogeneity within the PF-EPN-B ependymoma subgroup. Acta neuropathologica, 136(2), 227-237. https://doi.org/10.1007/s00401-018-1888-x

Cavalli, FMG, Hübner, JM, Sharma, T, Luu, B, Sill, M, Zapotocky, M, Mack, SC, Witt, H, Lin, T, Shih, DJH, Ho, B, Santi, M, Emery, L, Hukin, J, Dunham, C, McLendon, RE, Lipp, ES, Gururangan, S, Grossbach, A, French, P, Kros, JM, van Veelen, MLC, Rao, AAN, Giannini, C, Leary, S, Jung, S, Faria, CC, Mora, J, Schüller, U, Alonso, MM, Chan, JA, Klekner, A, Chambless, LB, Hwang, EI, Massimino, M, Eberhart, CG, Karajannis, MA, Lu, B, Liau, LM, Zollo, M, Ferrucci, V, Carlotti, C, Tirapelli, DPC, Tabori, U, Bouffet, E, Ryzhova, M, Ellison, DW, Merchant, TE, Gilbert, MR, Armstrong, TS, Korshunov, A, Pfister, SM, Taylor, MD, Aldape, K, Pajtler, KW, Kool, M & Ramaswamy, V 2018, 'Heterogeneity within the PF-EPN-B ependymoma subgroup', Acta neuropathologica, vol. 136, no. 2, pp. 227-237. https://doi.org/10.1007/s00401-018-1888-x

@article{fc04f739830f45e5b7f3533a9e86634b,

title = "Heterogeneity within the PF-EPN-B ependymoma subgroup",

abstract = "Posterior fossa ependymoma comprise three distinct molecular variants, termed PF-EPN-A (PFA), PF-EPN-B (PFB), and PF-EPN-SE (subependymoma). Clinically, they are very disparate and PFB tumors are currently being considered for a trial of radiation avoidance. However, to move forward, unraveling the heterogeneity within PFB would be highly desirable. To discern the molecular heterogeneity within PFB, we performed an integrated analysis consisting of DNA methylation profiling, copy-number profiling, gene expression profiling, and clinical correlation across a cohort of 212 primary posterior fossa PFB tumors. Unsupervised spectral clustering and t-SNE analysis of genome-wide methylation data revealed five distinct subtypes of PFB tumors, termed PFB1-5, with distinct demographics, copy-number alterations, and gene expression profiles. All PFB subtypes were distinct from PFA and posterior fossa subependymomas. Of the five subtypes, PFB4 and PFB5 are more discrete, consisting of younger and older patients, respectively, with a strong female-gender enrichment in PFB5 (age: p = 0.011, gender: p = 0.04). Broad copy-number aberrations were common; however, many events such as chromosome 2 loss, 5 gain, and 17 loss were enriched in specific subtypes and 1q gain was enriched in PFB1. Late relapses were common across all five subtypes, but deaths were uncommon and present in only two subtypes (PFB1 and PFB3). Unlike the case in PFA ependymoma, 1q gain was not a robust marker of poor progression-free survival; however, chromosome 13q loss may represent a novel marker for risk stratification across the spectrum of PFB subtypes. Similar to PFA ependymoma, there exists a significant intertumoral heterogeneity within PFB, with distinct molecular subtypes identified. Even when accounting for this heterogeneity, extent of resection remains the strongest predictor of poor outcome. However, this biological heterogeneity must be accounted for in future preclinical modeling and personalized therapies.",

keywords = "Clustering, Ependymoma, PFA, PFB, Posterior fossa, Subgrouping",

author = "Cavalli, {Florence M.G.} and H{\"u}bner, {Jens Martin} and Tanvi Sharma and Betty Luu and Martin Sill and Michal Zapotocky and Mack, {Stephen C.} and Hendrik Witt and Tong Lin and Shih, {David J.H.} and Ben Ho and Mariarita Santi and Lyndsey Emery and Juliette Hukin and Christopher Dunham and McLendon, {Roger E.} and Lipp, {Eric S.} and Sridharan Gururangan and Andrew Grossbach and Pim French and Kros, {Johan M.} and {van Veelen}, {Marie Lise C.} and Rao, {Amulya A.Nageswara} and Caterina Giannini and Sarah Leary and Shin Jung and Faria, {Claudia C.} and Jaume Mora and Ulrich Sch{\"u}ller and Alonso, {Marta M.} and Chan, {Jennifer A.} and Almos Klekner and Chambless, {Lola B.} and Hwang, {Eugene I.} and Maura Massimino and Eberhart, {Charles G.} and Karajannis, {Matthias A.} and Benjamin Lu and Liau, {Linda M.} and Massimo Zollo and Veronica Ferrucci and Carlos Carlotti and Tirapelli, {Daniela P.C.} and Uri Tabori and Eric Bouffet and Marina Ryzhova and Ellison, {David W.} and Merchant, {Thomas E.} and Gilbert, {Mark R.} and Armstrong, {Terri S.} and Andrey Korshunov and Pfister, {Stefan M.} and Taylor, {Michael D.} and Kenneth Aldape and Pajtler, {Kristian W.} and Marcel Kool and Vijay Ramaswamy",

note = "Funding Information: Acknowledgements VR is supported by operating funds from the Canadian Institutes of Health Research, American Brain Tumor Association, the Garron Family Cancer Center, Meagan{\textquoteright}s Walk, b.r.a.i.n.child, the Brain Tumor Foundation of Canada and a Collaborative Ependymoma Research Network (CERN) basic science fellowship. FMGC is supported by the Stephen Buttrum Brain Tumor Research Fellowship, granted by Brain Tumor Foundation of Canada. MZ is supported by Garron Family Cancer Center Fellowship, Meagan{\textquoteright}s Walk Neuro-Oncology Fellowship and Restracomp from Research Training Center at The Hospital for Sick Children. MDT is supported by funds from the Garron Family Chair in Childhood Cancer Research at The Hospital for Sick Children and The University of Toronto, and operating funds from the National Institutes of Health (R01CA159859 and R01CA148699), and the Pediatric Brain Tumor Foundation. EB is supported by funds from the Garron Family Chair in Childhood Cancer Research at The Hospital for Sick Children and The University of Toronto. This research was funded in part through the NIH/NCI Cancer Center Support Grant P30 CA008748 to Memorial Sloan Kettering Cancer Center. KWP is supported by a CERN Research Fellowship. Publisher Copyright: {\textcopyright} 2018, Springer-Verlag GmbH Germany, part of Springer Nature.",

year = "2018",

month = aug,

day = "1",

doi = "10.1007/s00401-018-1888-x",

language = "English (US)",

volume = "136",

pages = "227--237",

journal = "Acta Neuropathologica",

issn = "0001-6322",

publisher = "Springer Verlag",

number = "2",

}

TY - JOUR

T1 - Heterogeneity within the PF-EPN-B ependymoma subgroup

AU - Cavalli, Florence M.G.

AU - Hübner, Jens Martin

AU - Sharma, Tanvi

AU - Luu, Betty

AU - Sill, Martin

AU - Zapotocky, Michal

AU - Mack, Stephen C.

AU - Witt, Hendrik

AU - Lin, Tong

AU - Shih, David J.H.

AU - Ho, Ben

AU - Santi, Mariarita

AU - Emery, Lyndsey

AU - Hukin, Juliette

AU - Dunham, Christopher

AU - McLendon, Roger E.

AU - Lipp, Eric S.

AU - Gururangan, Sridharan

AU - Grossbach, Andrew

AU - French, Pim

AU - Kros, Johan M.

AU - van Veelen, Marie Lise C.

AU - Rao, Amulya A.Nageswara

AU - Giannini, Caterina

AU - Leary, Sarah

AU - Jung, Shin

AU - Faria, Claudia C.

AU - Mora, Jaume

AU - Schüller, Ulrich

AU - Alonso, Marta M.

AU - Chan, Jennifer A.

AU - Klekner, Almos

AU - Chambless, Lola B.

AU - Hwang, Eugene I.

AU - Massimino, Maura

AU - Eberhart, Charles G.

AU - Karajannis, Matthias A.

AU - Lu, Benjamin

AU - Liau, Linda M.

AU - Zollo, Massimo

AU - Ferrucci, Veronica

AU - Carlotti, Carlos

AU - Tirapelli, Daniela P.C.

AU - Tabori, Uri

AU - Bouffet, Eric

AU - Ryzhova, Marina

AU - Ellison, David W.

AU - Merchant, Thomas E.

AU - Gilbert, Mark R.

AU - Armstrong, Terri S.

AU - Korshunov, Andrey

AU - Pfister, Stefan M.

AU - Taylor, Michael D.

AU - Aldape, Kenneth

AU - Pajtler, Kristian W.

AU - Kool, Marcel

AU - Ramaswamy, Vijay

N1 - Funding Information: Acknowledgements VR is supported by operating funds from the Canadian Institutes of Health Research, American Brain Tumor Association, the Garron Family Cancer Center, Meagan’s Walk, b.r.a.i.n.child, the Brain Tumor Foundation of Canada and a Collaborative Ependymoma Research Network (CERN) basic science fellowship. FMGC is supported by the Stephen Buttrum Brain Tumor Research Fellowship, granted by Brain Tumor Foundation of Canada. MZ is supported by Garron Family Cancer Center Fellowship, Meagan’s Walk Neuro-Oncology Fellowship and Restracomp from Research Training Center at The Hospital for Sick Children. MDT is supported by funds from the Garron Family Chair in Childhood Cancer Research at The Hospital for Sick Children and The University of Toronto, and operating funds from the National Institutes of Health (R01CA159859 and R01CA148699), and the Pediatric Brain Tumor Foundation. EB is supported by funds from the Garron Family Chair in Childhood Cancer Research at The Hospital for Sick Children and The University of Toronto. This research was funded in part through the NIH/NCI Cancer Center Support Grant P30 CA008748 to Memorial Sloan Kettering Cancer Center. KWP is supported by a CERN Research Fellowship. Publisher Copyright: © 2018, Springer-Verlag GmbH Germany, part of Springer Nature.

PY - 2018/8/1

Y1 - 2018/8/1

N2 - Posterior fossa ependymoma comprise three distinct molecular variants, termed PF-EPN-A (PFA), PF-EPN-B (PFB), and PF-EPN-SE (subependymoma). Clinically, they are very disparate and PFB tumors are currently being considered for a trial of radiation avoidance. However, to move forward, unraveling the heterogeneity within PFB would be highly desirable. To discern the molecular heterogeneity within PFB, we performed an integrated analysis consisting of DNA methylation profiling, copy-number profiling, gene expression profiling, and clinical correlation across a cohort of 212 primary posterior fossa PFB tumors. Unsupervised spectral clustering and t-SNE analysis of genome-wide methylation data revealed five distinct subtypes of PFB tumors, termed PFB1-5, with distinct demographics, copy-number alterations, and gene expression profiles. All PFB subtypes were distinct from PFA and posterior fossa subependymomas. Of the five subtypes, PFB4 and PFB5 are more discrete, consisting of younger and older patients, respectively, with a strong female-gender enrichment in PFB5 (age: p = 0.011, gender: p = 0.04). Broad copy-number aberrations were common; however, many events such as chromosome 2 loss, 5 gain, and 17 loss were enriched in specific subtypes and 1q gain was enriched in PFB1. Late relapses were common across all five subtypes, but deaths were uncommon and present in only two subtypes (PFB1 and PFB3). Unlike the case in PFA ependymoma, 1q gain was not a robust marker of poor progression-free survival; however, chromosome 13q loss may represent a novel marker for risk stratification across the spectrum of PFB subtypes. Similar to PFA ependymoma, there exists a significant intertumoral heterogeneity within PFB, with distinct molecular subtypes identified. Even when accounting for this heterogeneity, extent of resection remains the strongest predictor of poor outcome. However, this biological heterogeneity must be accounted for in future preclinical modeling and personalized therapies.

AB - Posterior fossa ependymoma comprise three distinct molecular variants, termed PF-EPN-A (PFA), PF-EPN-B (PFB), and PF-EPN-SE (subependymoma). Clinically, they are very disparate and PFB tumors are currently being considered for a trial of radiation avoidance. However, to move forward, unraveling the heterogeneity within PFB would be highly desirable. To discern the molecular heterogeneity within PFB, we performed an integrated analysis consisting of DNA methylation profiling, copy-number profiling, gene expression profiling, and clinical correlation across a cohort of 212 primary posterior fossa PFB tumors. Unsupervised spectral clustering and t-SNE analysis of genome-wide methylation data revealed five distinct subtypes of PFB tumors, termed PFB1-5, with distinct demographics, copy-number alterations, and gene expression profiles. All PFB subtypes were distinct from PFA and posterior fossa subependymomas. Of the five subtypes, PFB4 and PFB5 are more discrete, consisting of younger and older patients, respectively, with a strong female-gender enrichment in PFB5 (age: p = 0.011, gender: p = 0.04). Broad copy-number aberrations were common; however, many events such as chromosome 2 loss, 5 gain, and 17 loss were enriched in specific subtypes and 1q gain was enriched in PFB1. Late relapses were common across all five subtypes, but deaths were uncommon and present in only two subtypes (PFB1 and PFB3). Unlike the case in PFA ependymoma, 1q gain was not a robust marker of poor progression-free survival; however, chromosome 13q loss may represent a novel marker for risk stratification across the spectrum of PFB subtypes. Similar to PFA ependymoma, there exists a significant intertumoral heterogeneity within PFB, with distinct molecular subtypes identified. Even when accounting for this heterogeneity, extent of resection remains the strongest predictor of poor outcome. However, this biological heterogeneity must be accounted for in future preclinical modeling and personalized therapies.

KW - Clustering

KW - Ependymoma

KW - PFA

KW - PFB

KW - Posterior fossa

KW - Subgrouping

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U2 - 10.1007/s00401-018-1888-x

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JO - Acta Neuropathologica

JF - Acta Neuropathologica

SN - 0001-6322

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ER -

Heterogeneity within the PF-EPN-B ependymoma subgroup

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