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PATH-03. Clinically Tractable Outcome Prediction of Group 3/4 Medulloblastoma Based on TPD52 Immunohistochemistry: a Multicohort Study
BACKGROUND: International consensus and the 2021 WHO classification recognize eight molecular subgroups among Group 3/4 medulloblastoma (representing ~60% of medulloblastoma). However, very few clinical centers worldwide possess the technical capabilities to determine DNA-methylation patterns or oth...
Autores principales: | , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Oxford University Press
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9164902/ http://dx.doi.org/10.1093/neuonc/noac079.587 |
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author | Delaidelli, Alberto Dunham, Christopher Santi, Mariarita Negri, Gian Luca Triscott, Joanna Zheludkova, Olga Golanov, Andrey Ryzhova, Marina Okonechnikov, Konstantin Schrimpf, Daniel Stichel, Damian Ellison, David von Deimling, Andreas Kool, Marcel Pfister, Stefan Ramaswamy, Vijay Taylor, Michael Korshunov, Andrey Sorensen, Poul |
author_facet | Delaidelli, Alberto Dunham, Christopher Santi, Mariarita Negri, Gian Luca Triscott, Joanna Zheludkova, Olga Golanov, Andrey Ryzhova, Marina Okonechnikov, Konstantin Schrimpf, Daniel Stichel, Damian Ellison, David von Deimling, Andreas Kool, Marcel Pfister, Stefan Ramaswamy, Vijay Taylor, Michael Korshunov, Andrey Sorensen, Poul |
author_sort | Delaidelli, Alberto |
collection | PubMed |
description | BACKGROUND: International consensus and the 2021 WHO classification recognize eight molecular subgroups among Group 3/4 medulloblastoma (representing ~60% of medulloblastoma). However, very few clinical centers worldwide possess the technical capabilities to determine DNA-methylation patterns or other molecular parameters of high-risk for Group 3/4 tumors. As a result, biomarker-driven risk stratification and therapy assignment constitutes a major challenge in medulloblastoma research. Here, we identify an immunohistochemistry (IHC) marker as a clinically tractable method for improved medulloblastoma risk-stratification. PATIENTS and METHODS: We bioinformatically analyzed published medulloblastoma transcriptomes and proteomes identifying as a potential biomarker TPD52, whose IHC prognostic value was validated across three Group 3/4 medulloblastoma clinical cohorts (n = 387) treated with conventional therapies. Risk stratification and prediction capability were computed utilizing uni- and multivariate survival analysis. Newly developed risk classifiers including TPD52 IHC were compared to state-of-the-art risk stratification schemes in terms of prediction error, area under the time-dependent receiver operating characteristic (ROC) curves and C-statistic. RESULTS: TPD52 IHC percentage positivity represents a significant independent predictor of early relapse and death for Group 3/4 medulloblastoma (HRs between 3.67-26.7 [95% CIs between 1.00-706.23], p = 0.05, 0.017 and 0.0058). Cross-validated survival models incorporating TPD52 IHC with clinical and molecular features (subgroup affiliation, MYC status) outperformed existing disease risk-stratification schemes, and reclassified ~50% of patients into more appropriate risk categories. Finally, interaction effect in multivariate analyses revealed that TPD52 immunopositivity could be a predictive indicator of poor response to chemotherapy (HR 12.66 [95% CI 3.53-45.40], p < 0.0001), suggesting important implication for therapeutic choices. CONCLUSION: The current study adds an important asset to improve risk-stratification for Group 3/4 medulloblastoma. Integration of TPD52 IHC in classification algorithms significantly improves outcome prediction and can be rapidly adopted for risk stratification on a global scale, independently of advanced but technically challenging molecular profiling techniques. |
format | Online Article Text |
id | pubmed-9164902 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Oxford University Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-91649022022-06-05 PATH-03. Clinically Tractable Outcome Prediction of Group 3/4 Medulloblastoma Based on TPD52 Immunohistochemistry: a Multicohort Study Delaidelli, Alberto Dunham, Christopher Santi, Mariarita Negri, Gian Luca Triscott, Joanna Zheludkova, Olga Golanov, Andrey Ryzhova, Marina Okonechnikov, Konstantin Schrimpf, Daniel Stichel, Damian Ellison, David von Deimling, Andreas Kool, Marcel Pfister, Stefan Ramaswamy, Vijay Taylor, Michael Korshunov, Andrey Sorensen, Poul Neuro Oncol Pathology/Classification BACKGROUND: International consensus and the 2021 WHO classification recognize eight molecular subgroups among Group 3/4 medulloblastoma (representing ~60% of medulloblastoma). However, very few clinical centers worldwide possess the technical capabilities to determine DNA-methylation patterns or other molecular parameters of high-risk for Group 3/4 tumors. As a result, biomarker-driven risk stratification and therapy assignment constitutes a major challenge in medulloblastoma research. Here, we identify an immunohistochemistry (IHC) marker as a clinically tractable method for improved medulloblastoma risk-stratification. PATIENTS and METHODS: We bioinformatically analyzed published medulloblastoma transcriptomes and proteomes identifying as a potential biomarker TPD52, whose IHC prognostic value was validated across three Group 3/4 medulloblastoma clinical cohorts (n = 387) treated with conventional therapies. Risk stratification and prediction capability were computed utilizing uni- and multivariate survival analysis. Newly developed risk classifiers including TPD52 IHC were compared to state-of-the-art risk stratification schemes in terms of prediction error, area under the time-dependent receiver operating characteristic (ROC) curves and C-statistic. RESULTS: TPD52 IHC percentage positivity represents a significant independent predictor of early relapse and death for Group 3/4 medulloblastoma (HRs between 3.67-26.7 [95% CIs between 1.00-706.23], p = 0.05, 0.017 and 0.0058). Cross-validated survival models incorporating TPD52 IHC with clinical and molecular features (subgroup affiliation, MYC status) outperformed existing disease risk-stratification schemes, and reclassified ~50% of patients into more appropriate risk categories. Finally, interaction effect in multivariate analyses revealed that TPD52 immunopositivity could be a predictive indicator of poor response to chemotherapy (HR 12.66 [95% CI 3.53-45.40], p < 0.0001), suggesting important implication for therapeutic choices. CONCLUSION: The current study adds an important asset to improve risk-stratification for Group 3/4 medulloblastoma. Integration of TPD52 IHC in classification algorithms significantly improves outcome prediction and can be rapidly adopted for risk stratification on a global scale, independently of advanced but technically challenging molecular profiling techniques. Oxford University Press 2022-06-03 /pmc/articles/PMC9164902/ http://dx.doi.org/10.1093/neuonc/noac079.587 Text en © The Author(s) 2022. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. https://creativecommons.org/licenses/by-nc/4.0/This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial License (https://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com |
spellingShingle | Pathology/Classification Delaidelli, Alberto Dunham, Christopher Santi, Mariarita Negri, Gian Luca Triscott, Joanna Zheludkova, Olga Golanov, Andrey Ryzhova, Marina Okonechnikov, Konstantin Schrimpf, Daniel Stichel, Damian Ellison, David von Deimling, Andreas Kool, Marcel Pfister, Stefan Ramaswamy, Vijay Taylor, Michael Korshunov, Andrey Sorensen, Poul PATH-03. Clinically Tractable Outcome Prediction of Group 3/4 Medulloblastoma Based on TPD52 Immunohistochemistry: a Multicohort Study |
title | PATH-03. Clinically Tractable Outcome Prediction of Group 3/4 Medulloblastoma Based on TPD52 Immunohistochemistry: a Multicohort Study |
title_full | PATH-03. Clinically Tractable Outcome Prediction of Group 3/4 Medulloblastoma Based on TPD52 Immunohistochemistry: a Multicohort Study |
title_fullStr | PATH-03. Clinically Tractable Outcome Prediction of Group 3/4 Medulloblastoma Based on TPD52 Immunohistochemistry: a Multicohort Study |
title_full_unstemmed | PATH-03. Clinically Tractable Outcome Prediction of Group 3/4 Medulloblastoma Based on TPD52 Immunohistochemistry: a Multicohort Study |
title_short | PATH-03. Clinically Tractable Outcome Prediction of Group 3/4 Medulloblastoma Based on TPD52 Immunohistochemistry: a Multicohort Study |
title_sort | path-03. clinically tractable outcome prediction of group 3/4 medulloblastoma based on tpd52 immunohistochemistry: a multicohort study |
topic | Pathology/Classification |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9164902/ http://dx.doi.org/10.1093/neuonc/noac079.587 |
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