EMBR-21. CLINICALLY TRACTABLE OUTCOME PREDICTION OF GROUP 3/4 MEDULLOBLASTOMA BASED ON TPD52 IMMUNOHISTOCHEMISTRY: A MULTICOHORT STUDY. (1st June 2021)

• Record Type: Journal Article
• Authors: Delaidelli, Alberto; Dunham, Christopher; Santi, Maria Rita; Negri, Gian Luca; Triscott, Joanna; Zheludkova, Olga; Golanov, Andrey; Ryzhova, Marina; Okonechnikov, Konstantin; Schrimpf, Daniel; Stichel, Damian; von Deimling, Andreas; Kool, Marcel; Pfister, Stefan; Ramaswamy, Vijay; Korshunov, Andrey; Taylor, Michael; Sorensen, Poul
• Is Part Of: Neuro-oncology. Volume 23(2021)Supplement 1
• Page Start: i10
• Page End: i10
• Publication Date: 2021-06-01
• Subjects: Brain Neoplasms -- Periodicals; Brain -- Tumors -- Periodicals; Brain -- Cancer -- Periodicals; Nervous system -- Cancer -- Periodicals; 616.99481
• DOI: 10.1093/neuonc/noab090.039
• Languages: English
• ISSNs: 1522-8517

Abstract

Abstract: Background: International consensus and the 2021 WHO classification recognize eight molecular subtypes among Group 3/4 medulloblastoma (representing ~60% of tumors). 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. Biomarker-driven prognostic stratification models identified were cross validated in different cohorts. Results: TPD52 IHC 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 features outperformed existing disease risk-stratification schemes, and reclassified ~50% of patients into more appropriate risk categories. Finally, TPD52 immunopositivity is 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 redefines the approach to risk-stratification in 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.