MDB-63. AN INTERNATIONAL META-ANALYSIS OF SHH MEDULLOBLASTOMA SUBTYPES DEFINES A CLINICALLY SIGNIFICANT HIGH-RISK VARIANT OF SHH-SUBTYPE 3

Abstract

Abstract BACKGROUND The distinction of MBSHH into four methylation-dependent subgroups was recognized by the WHO in 2021. However, these subgroups have not previously been defined by international experimental consensus and their clinico-molecular features and behavior have not formally been investigated in large cohorts. We aimed to robustly identify SHH subgroups through analysis of MBSHH with DNA-methylation profiling. METHODS A cohort of 683 MBSHH, confidently classified using the Heidelberg classifier v12.5, was assembled for analysis from multiple international studies. To define subgroups, we applied consensus sampling-based clustering approaches to tumor methylomes, including assessment of confidence in class-definition and inter-technique concordance. The clinico-molecular features of consensus subgroups were investigated. RESULTS Lowest complexity analysis supported the division of MBSHH into the 4 WHO-subtypes. SHH-1 and SHH-2 were associated with lower age and infrequent mutations of PTCH1/SUFU; SHH-2 was distinguished from SHH-1 by enriched MBEN histology, absence of chromosome 2 gain, less frequent metastasis and more favorable overall-survival. SHH-4 presented in older children and adults (3-57; median 24 years), and was primarily defined by mutations in U1-snRNA (67/72). Consensus analyses supported the division of SHH-subgroup-3 into three. Importantly, the SHH-3C subtype was associated with a coalescence of high-risk features (LCA histology, TP53mut, MYCNamp/GLI2amp) alongside 3p, 10q and 17p loss, and had dismal survival. The remaining SHH-3A/B subtypes were characterized by 9q loss, frequent focal amplifications of TERT and PPM1D, and equivalent better survival. CONCLUSIONS This study affirms the distinction of MBSHH into 4 major subgroups. For infant disease, SHH-2 is a favorable-risk marker. For childhood-MBSHH, the SHH-3C subtype provides a molecular definition of high-risk that subsumes other previously-defined high-risk disease markers (LCA, MYCNamp, TP53mut) into a unified high-risk disease group. The other SHH-3 subtypes behave similarly and are favorable-risk. These subtypes have potential to enhance molecularly-guided risk-stratification in routine diagnostics, to improve patient outcomes and quality-of-life.