TERT promoter mutation and chromosome 6 loss define a high-risk subtype of ependymoma evolving from posterior fossa subependymoma
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TERT promoter mutation and chromosome 6 loss define a high-risk subtype of ependymoma evolving from posterior fossa subependymoma. / Thomas, Christian; Thierfelder, Felix; Träger, Malte; Soschinski, Patrick; Müther, Michael; Edelmann, Dominic; Förster, Alexandra; Geiler, Carola; Kim, Hee-Yeong; Filipski, Katharina; Harter, Patrick N; Schittenhelm, Jens; Eckert, Franziska; Ntoulias, Georgios; May, Sven-Axel; Stummer, Walter; Onken, Julia; Vajkoczy, Peter; Schüller, Ulrich; Heppner, Frank L; Capper, David; Koch, Arend; Kaul, David; Paulus, Werner; Hasselblatt, Martin; Schweizer, Leonille.
In: ACTA NEUROPATHOL, Vol. 141, No. 6, 06.2021, p. 959-970.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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TY - JOUR
T1 - TERT promoter mutation and chromosome 6 loss define a high-risk subtype of ependymoma evolving from posterior fossa subependymoma
AU - Thomas, Christian
AU - Thierfelder, Felix
AU - Träger, Malte
AU - Soschinski, Patrick
AU - Müther, Michael
AU - Edelmann, Dominic
AU - Förster, Alexandra
AU - Geiler, Carola
AU - Kim, Hee-Yeong
AU - Filipski, Katharina
AU - Harter, Patrick N
AU - Schittenhelm, Jens
AU - Eckert, Franziska
AU - Ntoulias, Georgios
AU - May, Sven-Axel
AU - Stummer, Walter
AU - Onken, Julia
AU - Vajkoczy, Peter
AU - Schüller, Ulrich
AU - Heppner, Frank L
AU - Capper, David
AU - Koch, Arend
AU - Kaul, David
AU - Paulus, Werner
AU - Hasselblatt, Martin
AU - Schweizer, Leonille
PY - 2021/6
Y1 - 2021/6
N2 - Subependymomas are benign tumors characteristically encountered in the posterior fossa of adults that show distinct epigenetic profiles assigned to the molecular group "subependymoma, posterior fossa" (PFSE) of the recently established DNA methylation-based classification of central nervous system tumors. In contrast, most posterior fossa ependymomas exhibit a more aggressive biological behavior and are allocated to the molecular subgroups PFA or PFB. A subset of ependymomas shows epigenetic similarities with subependymomas, but the precise biology of these tumors and their potential relationships remain unknown. We therefore set out to characterize epigenetic traits, mutational profiles, and clinical outcomes of 50 posterior fossa ependymal tumors of the PFSE group. On histo-morphology, these tumors comprised 12 ependymomas, 14 subependymomas and 24 tumors with mixed ependymoma-subependymoma morphology. Mixed ependymoma-subependymoma tumors varied in their extent of ependymoma differentiation (2-95%) but consistently exhibited global epigenetic profiles of the PFSE group. Selective methylome analysis of microdissected tumor components revealed CpG signatures in mixed tumors that coalesce with their pure counterparts. Loss of chr6 (20/50 cases), as well as TERT mutations (21/50 cases), were frequent events enriched in tumors with pure ependymoma morphology (p < 0.001) and confined to areas with ependymoma differentiation in mixed tumors. Clinically, pure ependymoma phenotype, chr6 loss, and TERT mutations were associated with shorter progression-free survival (each p < 0.001). In conclusion, our results suggest that subependymomas may acquire genetic and epigenetic changes throughout tumor evolution giving rise to subclones with ependymoma morphology (resulting in mixed tumors) that eventually overpopulate the subependymoma component (pure PFSE ependymomas).
AB - Subependymomas are benign tumors characteristically encountered in the posterior fossa of adults that show distinct epigenetic profiles assigned to the molecular group "subependymoma, posterior fossa" (PFSE) of the recently established DNA methylation-based classification of central nervous system tumors. In contrast, most posterior fossa ependymomas exhibit a more aggressive biological behavior and are allocated to the molecular subgroups PFA or PFB. A subset of ependymomas shows epigenetic similarities with subependymomas, but the precise biology of these tumors and their potential relationships remain unknown. We therefore set out to characterize epigenetic traits, mutational profiles, and clinical outcomes of 50 posterior fossa ependymal tumors of the PFSE group. On histo-morphology, these tumors comprised 12 ependymomas, 14 subependymomas and 24 tumors with mixed ependymoma-subependymoma morphology. Mixed ependymoma-subependymoma tumors varied in their extent of ependymoma differentiation (2-95%) but consistently exhibited global epigenetic profiles of the PFSE group. Selective methylome analysis of microdissected tumor components revealed CpG signatures in mixed tumors that coalesce with their pure counterparts. Loss of chr6 (20/50 cases), as well as TERT mutations (21/50 cases), were frequent events enriched in tumors with pure ependymoma morphology (p < 0.001) and confined to areas with ependymoma differentiation in mixed tumors. Clinically, pure ependymoma phenotype, chr6 loss, and TERT mutations were associated with shorter progression-free survival (each p < 0.001). In conclusion, our results suggest that subependymomas may acquire genetic and epigenetic changes throughout tumor evolution giving rise to subclones with ependymoma morphology (resulting in mixed tumors) that eventually overpopulate the subependymoma component (pure PFSE ependymomas).
KW - Adult
KW - Aged
KW - Aged, 80 and over
KW - Chromosomes, Human, Pair 6/genetics
KW - DNA Methylation
KW - Ependymoma/classification
KW - Female
KW - Genetic Techniques
KW - Humans
KW - Infratentorial Neoplasms/classification
KW - Male
KW - Middle Aged
KW - Mutation
KW - Progression-Free Survival
KW - Promoter Regions, Genetic/genetics
KW - Telomerase/genetics
U2 - 10.1007/s00401-021-02300-8
DO - 10.1007/s00401-021-02300-8
M3 - SCORING: Journal article
C2 - 33755803
VL - 141
SP - 959
EP - 970
JO - ACTA NEUROPATHOL
JF - ACTA NEUROPATHOL
SN - 0001-6322
IS - 6
ER -
