Optimizing biomarkers for accurate ependymoma diagnosis,
prognostication, and stratification within International
Clinical Trials: A BIOMECA study

J 2023

Optimizing biomarkers for accurate ependymoma diagnosis, prognostication, and stratification within International Clinical Trials: A BIOMECA study

CHAPMAN, Rebecca J, David R GHASEMI, Felipe ANDREIUOLO, Valentina ZSCHERNACK, Tauziede Espariat ARNAULT et. al.

Basic information

Original name

Optimizing biomarkers for accurate ependymoma diagnosis, prognostication, and stratification within International Clinical Trials: A BIOMECA study

Authors

Edition

Neuro-Oncology, Cary, Oxford University Press, 2023, 1522-8517

Other information

Language

English

Type of outcome

Článek v odborném periodiku

Field of Study

30230 Other clinical medicine subjects

Country of publisher

United Kingdom of Great Britain and Northern Ireland

Confidentiality degree

není předmětem státního či obchodního tajemství

References:

SIOP

Impact factor

Impact factor: 15.900 in 2022

RIV identification code

RIV/00216224:90249/23:00132051

DOI

http://dx.doi.org/10.1093/neuonc/noad055

UT WoS

000989756200001

Keywords (in Czech)

brain tumors; biomarkers; Ependymoma; neuro-oncology; paediatric

Keywords in English

brain tumors; biomarkers; Ependymoma; neuro-oncology; paediatric

Abstract

V originále

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.

Links

90249, large research infrastructures

Name: CZECRIN IV

Citovat

CHAPMAN, Rebecca J, David R GHASEMI, Felipe ANDREIUOLO, Valentina ZSCHERNACK, Tauziede Espariat ARNAULT, Francesca R BUTTARELLI, Felice GIANGASPERO, Jacques GRILL, Christine HABERLER, Simon M L PAINE, Ian SCOTT, Thomas S JACQUES, Martin SILL, Stefan PFISTER, John-Paul KILDAY, Pierre LEBLOND, Maura MASSIMINO, Hendrik WITT, Piergiorgio MODENA, Pascale VARLET, Torsten PIETSCH, Richard G GRUNDY, Kristian W PAJTLER and Timothy A RITZMANN. Optimizing biomarkers for accurate ependymoma diagnosis, prognostication, and stratification within International Clinical Trials: A BIOMECA study. Neuro-Oncology. Cary: Oxford University Press, 2023, vol. 25, No 10, p. 1871-1882. ISSN 1522-8517. Available from: https://dx.doi.org/10.1093/neuonc/noad055.

@article{2330759,
   author = {Chapman, Rebecca J and Ghasemi, David R and Andreiuolo, Felipe and Zschernack, Valentina and Arnault, Tauziede Espariat and Buttarelli, Francesca R and Giangaspero, Felice and Grill, Jacques and Haberler, Christine and Paine, Simon M L and Scott, Ian and Jacques, Thomas S and Sill, Martin and Pfister, Stefan and Kilday, JohnandPaul and Leblond, Pierre and Massimino, Maura and Witt, Hendrik and Modena, Piergiorgio and Varlet, Pascale and Pietsch, Torsten and Grundy, Richard G and Pajtler, Kristian W and Ritzmann, Timothy A},
   article_location = {Cary},
   article_number = {10},
   doi = {http://dx.doi.org/10.1093/neuonc/noad055},
   keywords = {brain tumors; biomarkers; Ependymoma; neuro-oncology; paediatric},
   language = {eng},
   issn = {1522-8517},
   journal = {Neuro-Oncology},
   title = {Optimizing biomarkers for accurate ependymoma diagnosis, prognostication, and stratification within International Clinical Trials: A BIOMECA study},
   url = {https://academic.oup.com/neuro-oncology/article/25/10/1871/7076995},
   volume = {25},
   year = {2023}
}

TY  - JOUR
ID  - 2330759
AU  - Chapman, Rebecca J - Ghasemi, David R - Andreiuolo, Felipe - Zschernack, Valentina - Arnault, Tauziede Espariat - 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
PY  - 2023
TI  - Optimizing biomarkers for accurate ependymoma diagnosis, prognostication, and stratification within International Clinical Trials: A BIOMECA study
JF  - Neuro-Oncology
VL  - 25
IS  - 10
SP  - 1871-1882
EP  - 1871-1882
PB  - Oxford University Press
SN  - 15228517
KW  - brain tumors
KW  - biomarkers
KW  - Ependymoma
KW  - neuro-oncology
KW  - paediatric
UR  - https://academic.oup.com/neuro-oncology/article/25/10/1871/7076995
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.
ER  -

CHAPMAN, Rebecca J, David R GHASEMI, Felipe ANDREIUOLO, Valentina ZSCHERNACK, Tauziede Espariat ARNAULT, Francesca R BUTTARELLI, Felice GIANGASPERO, Jacques GRILL, Christine HABERLER, Simon M L PAINE, Ian SCOTT, Thomas S JACQUES, Martin SILL, Stefan PFISTER, John-Paul KILDAY, Pierre LEBLOND, Maura MASSIMINO, Hendrik WITT, Piergiorgio MODENA, Pascale VARLET, Torsten PIETSCH, Richard G GRUNDY, Kristian W PAJTLER and Timothy A RITZMANN. Optimizing biomarkers for accurate ependymoma diagnosis, prognostication, and stratification within International Clinical Trials: A BIOMECA study. \textit{Neuro-Oncology}. Cary: Oxford University Press, 2023, vol.~25, No~10, p.~1871-1882. ISSN~1522-8517. Available from: https://dx.doi.org/10.1093/neuonc/noad055.

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