Histologically distinct neuroepithelial tumors with histone 3 G34 mutation are molecularly similar and comprise a single nosologic entity
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Histologically distinct neuroepithelial tumors with histone 3 G34 mutation are molecularly similar and comprise a single nosologic entity. / Korshunov, Andrey; Capper, David; Reuss, David; Schrimpf, Daniel; Ryzhova, Marina; Hovestadt, Volker; Sturm, Dominik; Meyer, Jochen; Jones, Chris; Zheludkova, Olga; Kumirova, Ella; Golanov, Andrey; Kool, Marcel; Schüller, Ulrich; Mittelbronn, Michel; Hasselblatt, Martin; Schittenhelm, Jens; Reifenberger, Guido; Herold-Mende, Christel; Lichter, Peter; Deimling, Andreas; Pfister, Stefan M; Jones, David T W.
In: ACTA NEUROPATHOL, Vol. 131, No. 1, 01.2016, p. 137-46.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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TY - JOUR
T1 - Histologically distinct neuroepithelial tumors with histone 3 G34 mutation are molecularly similar and comprise a single nosologic entity
AU - Korshunov, Andrey
AU - Capper, David
AU - Reuss, David
AU - Schrimpf, Daniel
AU - Ryzhova, Marina
AU - Hovestadt, Volker
AU - Sturm, Dominik
AU - Meyer, Jochen
AU - Jones, Chris
AU - Zheludkova, Olga
AU - Kumirova, Ella
AU - Golanov, Andrey
AU - Kool, Marcel
AU - Schüller, Ulrich
AU - Mittelbronn, Michel
AU - Hasselblatt, Martin
AU - Schittenhelm, Jens
AU - Reifenberger, Guido
AU - Herold-Mende, Christel
AU - Lichter, Peter
AU - Deimling, Andreas
AU - Pfister, Stefan M
AU - Jones, David T W
PY - 2016/1
Y1 - 2016/1
N2 - In contrast to the relative morphological uniformity of histone H3 K27-mutant high-grade gliomas, H3 G34-mutant tumors present as a histopathologically heterogeneous group of neoplasms, with microscopic characteristics typical of either glioblastoma (GBM) or central nervous system primitive neuroectodermal tumors (CNS-PNET). In the current study, we performed an integrative clinical, histopathological and molecular analysis of 81 G34-mutant CNS tumors. Routinely prepared tumor tissues were investigated for genomic and epigenomic alterations. Despite their divergent histopathological appearance, CNS tumors with H3.3 G34 mutations displayed uniform epigenetic signatures, suggesting a single biological origin. Comparative cytogenetic analysis with other GBM subtypes disclosed a high frequency and high specificity of 3q and 4q loss across G34-mutant tumors. PDGFRA amplification was more common in cases with GBM than with PNET morphology (36 vs. 5 %, respectively), while CCND2 amplifications showed the opposite trend (5 vs. 27 %). Survival analysis revealed the presence of amplified oncogene(s) and MGMT methylation as independent prognostic markers for poor and favorable outcomes, respectively. No difference in outcome was found between morphological variants (GBM vs. PNET). Thus, different histological variants of G34-mutant CNS tumors likely comprise a single biological entity (high-grade glioma with H3 G34 mutation, HGG_G34), which should be outlined in future diagnostic and therapeutic classifications. Screening for H3.3 G34 mutation should therefore be recommended as a routine diagnostic marker for supratentorial CNS tumors across a broad histological spectrum.
AB - In contrast to the relative morphological uniformity of histone H3 K27-mutant high-grade gliomas, H3 G34-mutant tumors present as a histopathologically heterogeneous group of neoplasms, with microscopic characteristics typical of either glioblastoma (GBM) or central nervous system primitive neuroectodermal tumors (CNS-PNET). In the current study, we performed an integrative clinical, histopathological and molecular analysis of 81 G34-mutant CNS tumors. Routinely prepared tumor tissues were investigated for genomic and epigenomic alterations. Despite their divergent histopathological appearance, CNS tumors with H3.3 G34 mutations displayed uniform epigenetic signatures, suggesting a single biological origin. Comparative cytogenetic analysis with other GBM subtypes disclosed a high frequency and high specificity of 3q and 4q loss across G34-mutant tumors. PDGFRA amplification was more common in cases with GBM than with PNET morphology (36 vs. 5 %, respectively), while CCND2 amplifications showed the opposite trend (5 vs. 27 %). Survival analysis revealed the presence of amplified oncogene(s) and MGMT methylation as independent prognostic markers for poor and favorable outcomes, respectively. No difference in outcome was found between morphological variants (GBM vs. PNET). Thus, different histological variants of G34-mutant CNS tumors likely comprise a single biological entity (high-grade glioma with H3 G34 mutation, HGG_G34), which should be outlined in future diagnostic and therapeutic classifications. Screening for H3.3 G34 mutation should therefore be recommended as a routine diagnostic marker for supratentorial CNS tumors across a broad histological spectrum.
KW - Adolescent
KW - Adult
KW - Central Nervous System Neoplasms
KW - Child
KW - Epigenomics
KW - Female
KW - Glioblastoma
KW - Glioma
KW - Histones
KW - Humans
KW - Male
KW - Middle Aged
KW - Mutation
KW - Supratentorial Neoplasms
KW - Young Adult
KW - Journal Article
U2 - 10.1007/s00401-015-1493-1
DO - 10.1007/s00401-015-1493-1
M3 - SCORING: Journal article
C2 - 26482474
VL - 131
SP - 137
EP - 146
JO - ACTA NEUROPATHOL
JF - ACTA NEUROPATHOL
SN - 0001-6322
IS - 1
ER -