HOXD12 as an oncofetal protein expressed in WNT-activated medulloblastomas

Aberrant reactivation of embryonic patterning programs is a hallmark of cancer. We previously identified HOXD12 activation in aggressive oligodendrogliomas, but its broader significance across brain tumors remains unexamined. Here, we evaluated HOXD12 protein expression via immunohistochemistry in 162 primary CNS tumors and 84 brain metastases. HOXD12 expression was significantly enriched in primary CNS tumors over brain metastases (P < .0001). Among primary malignancies, medulloblastoma exhibited the highest HOXD12 expression compared to diffuse gliomas, ependymomas, and meningiomas (P < .0001). Conversely, HOXD12 levels did not vary by diffuse glioma subtype or metastatic site of origin. To resolve subgroup-specific patterns, we integrated whole-genome DNA methylation (n = 1338) and bulk RNA-sequencing (n = 876) datasets across medulloblastoma molecular subgroups. Multi-omic analysis revealed maximal HOXD12 gene body methylation and transcript expression specifically within the WNT-activated medulloblastoma subgroup (P < .0001). These findings demonstrate that HOXD12 reactivation is preferentially associated with primary CNS tumors and is highly pronounced in WNT-activated medulloblastomas. Our results position HOXD12 as a candidate immunohistochemical surrogate for the WNT-activated medulloblastoma subgroup.