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@ARTICLE{Gmez:132739,
author = {S. Gómez and A. Garrido-Garcia and L. Garcia-Gerique and
I. Lemos and M. Suñol and C. de Torres and M. Kulis and S.
Pérez-Jaume and Á. M. Carcaboso and B. Luu and M. W.
Kieran and N. Jabado and A. Kozlenkov and S. Dracheva and V.
Ramaswamy and V. Hovestadt$^*$ and P. Johann$^*$ and D.
Jones$^*$ and S. Pfister$^*$ and A. Morales La Madrid and O.
Cruz and M. D. Taylor and J.-I. Martin-Subero and J. Mora
and C. Lavarino},
title = {{A} {N}ovel {M}ethod for {R}apid {M}olecular {S}ubgrouping
of {M}edulloblastoma.},
journal = {Clinical cancer research},
volume = {24},
number = {6},
issn = {1557-3265},
address = {Philadelphia, Pa. [u.a.]},
publisher = {AACR},
reportid = {DKFZ-2018-00393},
pages = {1355 - 1363},
year = {2018},
abstract = {Purpose: The classification of medulloblastoma into WNT,
SHH, group 3, and group 4 subgroups has become of critical
importance for patient risk stratification and
subgroup-tailored clinical trials. Here, we aimed to develop
a simplified, clinically applicable classification approach
that can be implemented in the majority of centers treating
patients with medulloblastoma.Experimental Design: We
analyzed 1,577 samples comprising previously published DNA
methylation microarray data (913 medulloblastomas, 457
non-medulloblastoma tumors, 85 normal tissues), and 122
frozen and formalin-fixed paraffin-embedded medulloblastoma
samples. Biomarkers were identified applying stringent
selection filters and Linear Discriminant Analysis (LDA)
method, and validated using DNA methylation microarray data,
bisulfite pyrosequencing, and direct-bisulfite
sequencing.Results: Using a LDA-based approach, we developed
and validated a prediction method (EpiWNT-SHH classifier)
based on six epigenetic biomarkers that allowed for rapid
classification of medulloblastoma into the clinically
relevant subgroups WNT, SHH, and non-WNT/non-SHH with
excellent concordance $(>99\%)$ with current gold-standard
methods, DNA methylation microarray, and gene signature
profiling analysis. The EpiWNT-SHH classifier showed high
prediction capacity using both frozen and formalin-fixed
material, as well as diverse DNA methylation detection
methods. Similarly, we developed a classifier specific for
group 3 and group 4 tumors, based on five biomarkers
(EpiG3-G4) with good discriminatory capacity, allowing for
correct assignment of more than $92\%$ of tumors. EpiWNT-SHH
and EpiG3-G4 methylation profiles remained stable across
tumor primary, metastasis, and relapse samples.Conclusions:
The EpiWNT-SHH and EpiG3-G4 classifiers represent a new
simplified approach for accurate, rapid, and cost-effective
molecular classification of single medulloblastoma DNA
samples, using clinically applicable DNA methylation
detection methods. Clin Cancer Res; 24(6); 1355-63. ©2018
AACR.},
cin = {B060 / B062},
ddc = {610},
cid = {I:(DE-He78)B060-20160331 / I:(DE-He78)B062-20160331},
pnm = {312 - Functional and structural genomics (POF3-312)},
pid = {G:(DE-HGF)POF3-312},
typ = {PUB:(DE-HGF)16},
pubmed = {pmid:29351917},
doi = {10.1158/1078-0432.CCR-17-2243},
url = {https://inrepo02.dkfz.de/record/132739},
}