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Gene expression profiling of Group 3 medulloblastomas defines a clinically tractable stratification based on KIRREL2 expression

Medulloblastomas (MB) molecularly designated as Group 3 (Grp 3) MB represent a more clinically aggressive tumor variant which, as a group, displays heterogeneous molecular characteristics and disease outcomes. Reliable risk stratification of Grp 3 MB would allow for appropriate assignment of patient...

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Autores principales: Korshunov, Andrey, Okonechnikov, Konstantin, Stichel, Damian, Schrimpf, Daniel, Delaidelli, Alberto, Tonn, Svenja, Mynarek, Martin, Sievers, Philipp, Sahm, Felix, Jones, David T. W., von Deimling, Andreas, Pfister, Stefan M., Kool, Marcel
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Springer Berlin Heidelberg 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9288368/
https://www.ncbi.nlm.nih.gov/pubmed/35771282
http://dx.doi.org/10.1007/s00401-022-02460-1
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author Korshunov, Andrey
Okonechnikov, Konstantin
Stichel, Damian
Schrimpf, Daniel
Delaidelli, Alberto
Tonn, Svenja
Mynarek, Martin
Sievers, Philipp
Sahm, Felix
Jones, David T. W.
von Deimling, Andreas
Pfister, Stefan M.
Kool, Marcel
author_facet Korshunov, Andrey
Okonechnikov, Konstantin
Stichel, Damian
Schrimpf, Daniel
Delaidelli, Alberto
Tonn, Svenja
Mynarek, Martin
Sievers, Philipp
Sahm, Felix
Jones, David T. W.
von Deimling, Andreas
Pfister, Stefan M.
Kool, Marcel
author_sort Korshunov, Andrey
collection PubMed
description Medulloblastomas (MB) molecularly designated as Group 3 (Grp 3) MB represent a more clinically aggressive tumor variant which, as a group, displays heterogeneous molecular characteristics and disease outcomes. Reliable risk stratification of Grp 3 MB would allow for appropriate assignment of patients to aggressive treatment protocols and, vice versa, for sparing adverse effects of high-dose radio-chemotherapy in patients with standard or low-risk tumors. Here we performed RNA-based analysis on an international cohort of 179 molecularly designated Grp 3 MB treated with HIT protocols. We analyzed the clinical significance of differentially expressed genes, thereby developing optimal prognostic subdivision of this MB molecular group. We compared the transcriptome profiles of two Grp 3 MB subsets with various outcomes (76 died within the first 60 months vs. 103 survived this period) and identified 224 differentially expressed genes (DEG) between these two clinical groups (Limma R algorithm, adjusted p-value < 0.05). We selected the top six DEG overexpressed in the unfavorable cohort for further survival analysis and found that expression of all six genes strongly correlated with poor outcomes. However, only high expression of KIRREL2 was identified as an independent molecular prognostic indicator of poor patients’ survival. Based on clinical and molecular patterns, four risk categories were outlined for Grp 3 MB patients: i. low-risk: M0-1/MYC non-amplified/KIRREL2 low (n = 48; 5-year OS—95%); ii. standard-risk: M0-1/MYC non-amplified/KIRREL2 high or M2-3/MYC non-amplified/KIRREL2 low (n = 65; 5-year OS—70%); iii. high-risk: M2-3/MYC non-amplified/KIRREL2 high (n = 36; 5-year OS—30%); iv. very high risk—all MYC amplified tumors (n = 30; 5-year OS—0%). Cross-validated survival models incorporating KIRREL2 expression with clinical features allowed for the reclassification of up to 50% of Grp 3 MB patients into a more appropriate risk category. Finally, KIRREL2 immunopositivity was also identified as a predictive indicator of Grp 3 MB poor survival, thus suggesting its application as a possible prognostic marker in routine clinical settings. Our results indicate that integration of KIRREL2 expression in risk stratification models may improve Grp 3 MB outcome prediction. Therefore, simple gene and/or protein expression analyses for this molecular marker could be easily adopted for Grp 3 MB prognostication and may help in assigning patients to optimal therapeutic approaches in prospective clinical trials. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s00401-022-02460-1.
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spelling pubmed-92883682022-07-18 Gene expression profiling of Group 3 medulloblastomas defines a clinically tractable stratification based on KIRREL2 expression Korshunov, Andrey Okonechnikov, Konstantin Stichel, Damian Schrimpf, Daniel Delaidelli, Alberto Tonn, Svenja Mynarek, Martin Sievers, Philipp Sahm, Felix Jones, David T. W. von Deimling, Andreas Pfister, Stefan M. Kool, Marcel Acta Neuropathol Original Paper Medulloblastomas (MB) molecularly designated as Group 3 (Grp 3) MB represent a more clinically aggressive tumor variant which, as a group, displays heterogeneous molecular characteristics and disease outcomes. Reliable risk stratification of Grp 3 MB would allow for appropriate assignment of patients to aggressive treatment protocols and, vice versa, for sparing adverse effects of high-dose radio-chemotherapy in patients with standard or low-risk tumors. Here we performed RNA-based analysis on an international cohort of 179 molecularly designated Grp 3 MB treated with HIT protocols. We analyzed the clinical significance of differentially expressed genes, thereby developing optimal prognostic subdivision of this MB molecular group. We compared the transcriptome profiles of two Grp 3 MB subsets with various outcomes (76 died within the first 60 months vs. 103 survived this period) and identified 224 differentially expressed genes (DEG) between these two clinical groups (Limma R algorithm, adjusted p-value < 0.05). We selected the top six DEG overexpressed in the unfavorable cohort for further survival analysis and found that expression of all six genes strongly correlated with poor outcomes. However, only high expression of KIRREL2 was identified as an independent molecular prognostic indicator of poor patients’ survival. Based on clinical and molecular patterns, four risk categories were outlined for Grp 3 MB patients: i. low-risk: M0-1/MYC non-amplified/KIRREL2 low (n = 48; 5-year OS—95%); ii. standard-risk: M0-1/MYC non-amplified/KIRREL2 high or M2-3/MYC non-amplified/KIRREL2 low (n = 65; 5-year OS—70%); iii. high-risk: M2-3/MYC non-amplified/KIRREL2 high (n = 36; 5-year OS—30%); iv. very high risk—all MYC amplified tumors (n = 30; 5-year OS—0%). Cross-validated survival models incorporating KIRREL2 expression with clinical features allowed for the reclassification of up to 50% of Grp 3 MB patients into a more appropriate risk category. Finally, KIRREL2 immunopositivity was also identified as a predictive indicator of Grp 3 MB poor survival, thus suggesting its application as a possible prognostic marker in routine clinical settings. Our results indicate that integration of KIRREL2 expression in risk stratification models may improve Grp 3 MB outcome prediction. Therefore, simple gene and/or protein expression analyses for this molecular marker could be easily adopted for Grp 3 MB prognostication and may help in assigning patients to optimal therapeutic approaches in prospective clinical trials. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s00401-022-02460-1. Springer Berlin Heidelberg 2022-06-30 2022 /pmc/articles/PMC9288368/ /pubmed/35771282 http://dx.doi.org/10.1007/s00401-022-02460-1 Text en © The Author(s) 2022 https://creativecommons.org/licenses/by/4.0/Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Original Paper
Korshunov, Andrey
Okonechnikov, Konstantin
Stichel, Damian
Schrimpf, Daniel
Delaidelli, Alberto
Tonn, Svenja
Mynarek, Martin
Sievers, Philipp
Sahm, Felix
Jones, David T. W.
von Deimling, Andreas
Pfister, Stefan M.
Kool, Marcel
Gene expression profiling of Group 3 medulloblastomas defines a clinically tractable stratification based on KIRREL2 expression
title Gene expression profiling of Group 3 medulloblastomas defines a clinically tractable stratification based on KIRREL2 expression
title_full Gene expression profiling of Group 3 medulloblastomas defines a clinically tractable stratification based on KIRREL2 expression
title_fullStr Gene expression profiling of Group 3 medulloblastomas defines a clinically tractable stratification based on KIRREL2 expression
title_full_unstemmed Gene expression profiling of Group 3 medulloblastomas defines a clinically tractable stratification based on KIRREL2 expression
title_short Gene expression profiling of Group 3 medulloblastomas defines a clinically tractable stratification based on KIRREL2 expression
title_sort gene expression profiling of group 3 medulloblastomas defines a clinically tractable stratification based on kirrel2 expression
topic Original Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9288368/
https://www.ncbi.nlm.nih.gov/pubmed/35771282
http://dx.doi.org/10.1007/s00401-022-02460-1
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