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 - 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
DO - 10.1007/s00401-018-1888-x
M3 - Article
C2 - 30019219
AN - SCOPUS:85049943373
SN - 0001-6322
VL - 136
SP - 227
EP - 237
JO - Acta neuropathologica
JF - Acta neuropathologica
IS - 2
ER -