Authors: 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, Poul H. Sorensen
Summary: Purpose: International consensus and the 2021 WHO classification recognize eight molecular subgroups among non-WNT/non-SHH (Group 3/4) medulloblastoma, representing ~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 immunohistochemistry (IHC) marker as a clinically tractable method for improved medulloblastoma risk stratification.
Experimental Design: 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.
Results: TPD52 IHC positivity represented 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 state-of-the-art risk stratification schemes, and reclassified ~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.
Conclusions: The current study redefines the approach to risk stratification in Group 3/4 medulloblastoma in global practice. Since 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.
Source: Clinical Cancer Research, 2021; clincanres.2057.2021