Abstract

Background: Accurate identification of medulloblastoma molecular subgroups is essential, particularly in settings lacking advanced genomic tools. Conventional markers, such as β-catenin, present significant challenges in reliably detecting the WNT-activated subgroup (WNT-AG).

Aims: To evaluate the utility of lymphoid enhancer-binding factor 1 (LEF1), Cyclin D1, and receptor tyrosine kinase-like orphan receptor 2 (ROR2) as immunohistochemical (IHC) markers for molecular subgroup classification and to assess their prognostic significance.

Study Design: Retrospective cohort study.

Methods: IHC analysis was performed using LEF1, Cyclin D1, and ROR2. Two distinct LEF1 staining patterns were identified: nuclear (nLEF1) and punctate (pLEF1). A subset of 29 cases, selected based on predefined criteria, underwent EPIC array Methylation analysis. Findings were correlated with recurrence and survival outcomes.

Results: Among the 94 cases, 12.8% were WNT-AG, 54.3% were sonic hedgehog-activated subgroup (SHH-AG), and 33.0% were Groups 3 and 4 (G3/4). nLEF1 demonstrated higher specificity and sensitivity for WNT-AG than β-catenin, identifying it as a more reliable diagnostic marker. High pLEF1 expression was strongly associated with SHH-AG. Cyclin D1 positivity was predominantly observed in WNT-AG. While ROR2 did not identify WNT-AG effectively, its absence in Group 3 cases was notable. Prognostic analysis revealed that LEF1 expression patterns correlated with favorable survival outcomes: total LEF1 (tLEF1) and nLEF1 were associated with improved overall survival, whereas pLEF1 and tLEF1 were linked to better progression-free survival.

Conclusion: Nuclear LEF1 (nLEF1) is at least as effective as β-Catenin in identifying WNT-AG and may serve as a superior diagnostic marker. Cyclin D1 can be used as a complementary marker in WNT-AG detection. ROR2 negativity may indicate G3 tumors, though further studies are warranted to confirm its prognostic value.