Optimizing biomarkers for accurate ependymoma diagnosis, prognostication, and stratification within International Clinical Trials: A BIOMECA study.
Ependymoma
biomarkers
brain tumors
neuro-oncology
paediatric
Journal
Neuro-oncology
ISSN: 1523-5866
Titre abrégé: Neuro Oncol
Pays: England
ID NLM: 100887420
Informations de publication
Date de publication:
03 10 2023
03 10 2023
Historique:
medline:
5
10
2023
pubmed:
15
3
2023
entrez:
14
3
2023
Statut:
ppublish
Résumé
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. 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. 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. 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.
Sections du résumé
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.
Identifiants
pubmed: 36916248
pii: 7076995
doi: 10.1093/neuonc/noad055
pmc: PMC10547510
doi:
Substances chimiques
Histones
0
Tenascin
0
Biomarkers
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1871-1882Subventions
Organisme : Cancer Research UK
Pays : United Kingdom
Informations de copyright
© The Author(s) 2023. Published by Oxford University Press on behalf of the Society for Neuro-Oncology.
Références
Sci Transl Med. 2016 Nov 23;8(366):366ra161
pubmed: 27881822
Genome Res. 2021 Mar;31(3):448-460
pubmed: 33441414
J Clin Oncol. 2010 Jul 1;28(19):3182-90
pubmed: 20516456
Neuro Oncol. 2022 Jun 1;24(6):936-948
pubmed: 35018471
Acta Neuropathol. 2018 Aug;136(2):211-226
pubmed: 29909548
Future Oncol. 2013 Feb;9(2):183-91
pubmed: 23414469
Lancet Oncol. 2009 Mar;10(3):258-66
pubmed: 19274783
Lancet Oncol. 2007 Aug;8(8):696-705
pubmed: 17644039
Acta Neuropathol. 2014 Apr;127(4):609-11
pubmed: 24562983
Acta Neuropathol. 2018 Aug;136(2):227-237
pubmed: 30019219
Cancer Genet. 2012 Jul-Aug;205(7-8):341-55
pubmed: 22867995
Acta Neuropathol. 2020 Feb;139(2):305-318
pubmed: 31679042
Front Neurol. 2022 Jun 02;13:887544
pubmed: 35720069
Neuro Oncol. 2016 Oct;18(10):1451-60
pubmed: 27194148
J Clin Oncol. 2001 Mar 1;19(5):1288-96
pubmed: 11230470
Acta Neuropathol Commun. 2019 Feb 20;7(1):24
pubmed: 30786920
Acta Neuropathol Commun. 2019 Nov 14;7(1):181
pubmed: 31727173
Acta Neuropathol. 2021 Mar;141(3):455-466
pubmed: 33481105
Cancer Discov. 2021 Sep;11(9):2200-2215
pubmed: 33741710
Pediatr Blood Cancer. 2020 Sep;67(9):e28426
pubmed: 32614133
Cancer Cell. 2015 May 11;27(5):728-43
pubmed: 25965575
Cancer Discov. 2021 Sep;11(9):2216-2229
pubmed: 33741711
Acta Neuropathol. 2021 Nov;142(5):827-839
pubmed: 34355256
Acta Neuropathol. 2012 Aug;124(2):247-57
pubmed: 22526017
J Pathol. 2020 Apr;250(5):510-517
pubmed: 32057098
Acta Neuropathol. 2017 Nov;134(5):705-714
pubmed: 28733933
Neuro Oncol. 2018 Nov 12;20(12):1616-1624
pubmed: 30053291
Acta Neuropathol Commun. 2018 Dec 4;6(1):134
pubmed: 30514397
Cancer. 2019 Jun 1;125(11):1867-1876
pubmed: 30768777
Nature. 2014 Feb 27;506(7489):451-5
pubmed: 24553141
Acta Neuropathol Commun. 2016 Aug 22;4(1):88
pubmed: 27550150
Acta Neuropathol Commun. 2015 Dec 15;3:85
pubmed: 26671581
Am J Pathol. 2002 Dec;161(6):2133-41
pubmed: 12466129
Cancer. 2017 Jul 1;123(13):2570-2578
pubmed: 28267208
Brain Pathol. 2016 Jul;26(4):551-4
pubmed: 27062283
Brain Pathol. 2019 May;29(3):325-335
pubmed: 30325077
Neurosurgery. 2017 Jul 1;81(1):N7-N8
pubmed: 28873995
Brain Pathol. 2020 Sep;30(5):863-866
pubmed: 32502305
PLoS One. 2017 Jun 15;12(6):e0178351
pubmed: 28617804
Am J Surg Pathol. 2019 Jan;43(1):56-63
pubmed: 29266023
Cancer Cell. 2011 Aug 16;20(2):143-57
pubmed: 21840481
Cancer Discov. 2021 Sep;11(9):2230-2247
pubmed: 33879448
Theriogenology. 2010 Jun;73(9):1167-79
pubmed: 20138353