Optimizing biomarkers for accurate ependymoma diagnosis, prognostication, and stratification within International Clinical Trials: A BIOMECA study
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Optimizing biomarkers for accurate ependymoma diagnosis, prognostication, and stratification within International Clinical Trials: A BIOMECA study. / Chapman, Rebecca J; Ghasemi, David R; Andreiuolo, Felipe; Zschernack, Valentina; Espariat, Arnault Tauziede; Buttarelli, Francesca R; Giangaspero, Felice; Grill, Jacques; Haberler, Christine; Paine, Simon M L; Scott, Ian; Jacques, Thomas S; Sill, Martin; Pfister, Stefan; Kilday, John-Paul; Leblond, Pierre; Massimino, Maura; Witt, Hendrik; Modena, Piergiorgio; Varlet, Pascale; Pietsch, Torsten; Grundy, Richard G; Pajtler, Kristian W; Ritzmann, Timothy A.
In: NEURO-ONCOLOGY, Vol. 25, No. 10, 03.10.2023, p. 1871-1882.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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TY - JOUR
T1 - Optimizing biomarkers for accurate ependymoma diagnosis, prognostication, and stratification within International Clinical Trials: A BIOMECA study
AU - Chapman, Rebecca J
AU - Ghasemi, David R
AU - Andreiuolo, Felipe
AU - Zschernack, Valentina
AU - Espariat, Arnault Tauziede
AU - Buttarelli, Francesca R
AU - Giangaspero, Felice
AU - Grill, Jacques
AU - Haberler, Christine
AU - Paine, Simon M L
AU - Scott, Ian
AU - Jacques, Thomas S
AU - Sill, Martin
AU - Pfister, Stefan
AU - Kilday, John-Paul
AU - Leblond, Pierre
AU - Massimino, Maura
AU - Witt, Hendrik
AU - Modena, Piergiorgio
AU - Varlet, Pascale
AU - Pietsch, Torsten
AU - Grundy, Richard G
AU - Pajtler, Kristian W
AU - Ritzmann, Timothy A
N1 - © The Author(s) 2023. Published by Oxford University Press on behalf of the Society for Neuro-Oncology.
PY - 2023/10/3
Y1 - 2023/10/3
N2 - BACKGROUND: Accurate identification of brain tumor molecular subgroups is increasingly important. We aimed to establish the most accurate and reproducible ependymoma subgroup biomarker detection techniques, across 147 cases from International Society of Pediatric Oncology (SIOP) Ependymoma II trial participants, enrolled in the pan-European "Biomarkers of Ependymoma in Children and Adolescents (BIOMECA)" study.METHODS: Across 6 European BIOMECA laboratories, we evaluated epigenetic profiling (DNA methylation array); immunohistochemistry (IHC) for nuclear p65-RELA, H3K27me3, and Tenascin-C; copy number analysis via fluorescent in situ hybridization (FISH) and MLPA (1q, CDKN2A), and MIP and DNA methylation array (genome-wide copy number evaluation); analysis of ZFTA- and YAP1-fusions by RT-PCR and sequencing, Nanostring and break-apart FISH.RESULTS: DNA Methylation profiling classified 65.3% (n = 96/147) of cases as EPN-PFA and 15% (n = 22/147) as ST-ZFTA fusion-positive. Immunohistochemical loss of H3K27me3 was a reproducible and accurate surrogate marker for EPN-PFA (sensitivity 99%-100% across 3 centers). IHC for p65-RELA, FISH, and RNA-based analyses effectively identified ZFTA- and YAP-fused supratentorial ependymomas. Detection of 1q gain using FISH exhibited only 57% inter-center concordance and low sensitivity and specificity while MIP, MLPA, and DNA methylation-based approaches demonstrated greater accuracy.CONCLUSIONS: We confirm, in a prospective trial cohort, that H3K27me3 immunohistochemistry is a robust EPN-PFA biomarker. Tenascin-C should be abandoned as a PFA marker. DNA methylation and MIP arrays are effective tools for copy number analysis of 1q gain, 6q, and CDKN2A loss while FISH is inadequate. Fusion detection was successful, but rare novel fusions need more extensive technologies. Finally, we propose test sets to guide future diagnostic approaches.
AB - BACKGROUND: Accurate identification of brain tumor molecular subgroups is increasingly important. We aimed to establish the most accurate and reproducible ependymoma subgroup biomarker detection techniques, across 147 cases from International Society of Pediatric Oncology (SIOP) Ependymoma II trial participants, enrolled in the pan-European "Biomarkers of Ependymoma in Children and Adolescents (BIOMECA)" study.METHODS: Across 6 European BIOMECA laboratories, we evaluated epigenetic profiling (DNA methylation array); immunohistochemistry (IHC) for nuclear p65-RELA, H3K27me3, and Tenascin-C; copy number analysis via fluorescent in situ hybridization (FISH) and MLPA (1q, CDKN2A), and MIP and DNA methylation array (genome-wide copy number evaluation); analysis of ZFTA- and YAP1-fusions by RT-PCR and sequencing, Nanostring and break-apart FISH.RESULTS: DNA Methylation profiling classified 65.3% (n = 96/147) of cases as EPN-PFA and 15% (n = 22/147) as ST-ZFTA fusion-positive. Immunohistochemical loss of H3K27me3 was a reproducible and accurate surrogate marker for EPN-PFA (sensitivity 99%-100% across 3 centers). IHC for p65-RELA, FISH, and RNA-based analyses effectively identified ZFTA- and YAP-fused supratentorial ependymomas. Detection of 1q gain using FISH exhibited only 57% inter-center concordance and low sensitivity and specificity while MIP, MLPA, and DNA methylation-based approaches demonstrated greater accuracy.CONCLUSIONS: We confirm, in a prospective trial cohort, that H3K27me3 immunohistochemistry is a robust EPN-PFA biomarker. Tenascin-C should be abandoned as a PFA marker. DNA methylation and MIP arrays are effective tools for copy number analysis of 1q gain, 6q, and CDKN2A loss while FISH is inadequate. Fusion detection was successful, but rare novel fusions need more extensive technologies. Finally, we propose test sets to guide future diagnostic approaches.
KW - Child
KW - Adolescent
KW - Humans
KW - Histones/genetics
KW - Tenascin/genetics
KW - In Situ Hybridization, Fluorescence
KW - Prospective Studies
KW - Biomarkers
KW - Ependymoma/diagnosis
U2 - 10.1093/neuonc/noad055
DO - 10.1093/neuonc/noad055
M3 - SCORING: Journal article
C2 - 36916248
VL - 25
SP - 1871
EP - 1882
JO - NEURO-ONCOLOGY
JF - NEURO-ONCOLOGY
SN - 1522-8517
IS - 10
ER -
