Chromosomal Translocation of Protamine 1 Leads to a Patched 1 Deficiency During Medulloblastoma Tumorigenesis

Abstract

Pediatric medulloblastoma (MB) is a cerebellar brain tumor namely characterized by its origination in early development, as early as embryogenesis. MB is thought to originate from the highly heterogeneous granular neuron precursor (GNP) cell population that resides within the rhombic lip of the dorsal hindbrain region, and is particularly susceptible to the effects of the oncogenic Sonic Hedgehog (SHH) signaling pathway. Patched 1 (Ptch1), typically a transmembrane SHH pathway tumor suppressor gene, is mutated in 20% of MB cases, otherwise known as SHH-group MBs. This mutation in MB presents as a loss of heterozygosity (LOH), where the wild type allele of Ptch 1 is deleted. Ptch 1 receptor silencing activates downstream target genes such as proto-oncogene Smoothened (Smo) and allows for the initiation of tumorigenesis. However, the molecular basis for Ptch1 LOH in MB remains elusive. We have discovered a cancer-testis antigen, Protamine 1 (Prm 1), that is present in the Ptch 1 locus in SHH-group MB tumors. By utilization of the RNAscope technique, we confirm mRNA expression of Prm 1 in cerebellar tumor tissue, predominantly from tumor cells, but not in stromal cells. These studies reveal that tumor cells highjack the promoter of Ptch 1 to express Prm 1, promoting tumor progression. These findings establish the mechanism for Ptch 1 LOH in SHH-group MB, and provide the rationale to define the cell of origin for SHH group MB based on Prm 1 expression.