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Clinically tractable outcome prediction of non-WNT/non-SHH medulloblastoma based on TPD52 IHC in a multicohort study

International consensus and the 2021 WHO classification recognize eight molecular subgroups among non-WNT/non-SHH (Group 3/4) medulloblastoma, representing approximately 60% of tumors. However, very few clinical centers worldwide possess the technical capabilities to determine DNA methylation profil...

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Main Authors: Delaidelli, Alberto (Author) , Dunham, Christopher (Author) , Santi, Mariarita (Author) , Negri, Gian Luca (Author) , Triscott, Joanna (Author) , Zheludkova, Olga (Author) , Golanov, Andrey (Author) , Ryzhova, Marina (Author) , Okonechnikov, Konstantin (Author) , Schrimpf, Daniel (Author) , Stichel, Damian (Author) , Ellison, David W. (Author) , Deimling, Andreas von (Author) , Kool, Marcel (Author) , Pfister, Stefan (Author) , Ramaswamy, Vijay (Author) , Korshunov, Andrey (Author) , Taylor, Michael D. (Author) , Sorensen, Poul H. (Author)
Format: Article (Journal)
Language:English
Published: January 05 2022
In: Clinical cancer research
Year: 2022, Volume: 28, Issue: 1, Pages: 116-128
ISSN:1557-3265
DOI:10.1158/1078-0432.CCR-21-2057
Online Access:Verlag, lizenzpflichtig, Volltext: https://doi.org/10.1158/1078-0432.CCR-21-2057
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Author Notes:Alberto Delaidelli, Christopher Dunham, Mariarita Santi, Gian Luca Negri, Joanna Triscott, Olga Zheludkova, Andrey Golanov, Marina Ryzhova, Konstantin Okonechnikov, Daniel Schrimpf, Damian Stichel, David W. Ellison, Andreas von Deimling, Marcel Kool, Stefan M. Pfister, Vijay Ramaswamy, Andrey Korshunov, Michael D. Taylor, and Poul H. Sorensen
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Summary:International consensus and the 2021 WHO classification recognize eight molecular subgroups among non-WNT/non-SHH (Group 3/4) medulloblastoma, representing approximately 60% of tumors. However, very few clinical centers worldwide possess the technical capabilities to determine DNA methylation profiles 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 IHC marker as a clinically tractable method for improved medulloblastoma risk stratification.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.TPD52 IHC positivity represented a significant independent predictor of early relapse and death for group 3/4 medulloblastoma [HRs between 3.67 and 26.7; 95% confidence interval (CI) between 1.00 and 706.23; P = 0.05, 0.017, and 0.0058]. Cross-validated survival models incorporating TPD52 IHC with clinical features outperformed existing state-of-the-art risk stratification schemes, and reclassified approximately 50% of patients into more appropriate risk categories. Finally, TPD52 immunopositivity was 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.This study redefines the approach to risk stratification in group 3/4 medulloblastoma in global practice. Because integration of TPD52 IHC in classification algorithms significantly improved outcome prediction, this test could be rapidly adopted for risk stratification on a global scale, independently of advanced but technically challenging molecular profiling techniques.
Item Description:Gesehen am 02.09.2022
Physical Description:Online Resource
ISSN:1557-3265
DOI:10.1158/1078-0432.CCR-21-2057

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