TY - JOUR
T1 - Clinically Tractable Outcome Prediction of Non-WNT/Non-SHH Medulloblastoma Based on TPD52 IHC in a Multicohort Study
AU - Delaidelli, Alberto
AU - Dunham, Christopher
AU - Santi, Mariarita
AU - Negri, Gian Luca
AU - Triscott, Joanna
AU - Zheludkova, Olga
AU - Golanov, Andrey
AU - Ryzhova, Marina
AU - Okonechnikov, Konstantin
AU - Schrimpf, Daniel
AU - Stichel, Damian
AU - Ellison, David W.
AU - von Deimling, Andreas
AU - Kool, Marcel
AU - Pfister, Stefan M.
AU - Ramaswamy, Vijay
AU - Korshunov, Andrey
AU - Taylor, Michael D.
AU - Sorensen, Poul H.
N1 - ©2021 American Association for Cancer Research.
PY - 2022/1/1
Y1 - 2022/1/1
N2 - PURPOSE: 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.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 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.
CONCLUSIONS: 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.
AB - PURPOSE: 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.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 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.
CONCLUSIONS: 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.
KW - Biomarkers, Tumor/genetics
KW - Cerebellar Neoplasms/diagnosis
KW - Humans
KW - Immunohistochemistry
KW - Medulloblastoma/diagnosis
KW - Neoplasm Proteins
KW - Prognosis
KW - Transcription Factors
UR - http://www.scopus.com/inward/record.url?scp=85123075777&partnerID=8YFLogxK
UR - https://www.mendeley.com/catalogue/44edc755-d08e-38b9-b7b0-decf3dc43248/
U2 - 10.1158/1078-0432.CCR-21-2057
DO - 10.1158/1078-0432.CCR-21-2057
M3 - Article
C2 - 34702771
AN - SCOPUS:85123075777
SN - 1078-0432
VL - 28
SP - 116
EP - 128
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 1
ER -