Germline GPR161 Mutations Predispose to Pediatric Medulloblastoma

The identification of a heritable tumor predisposition often leads to changes in management and increased surveillance of individuals who are at risk; however, for many rare entities, our knowledge of heritable predisposition is incomplete. Families with childhood medulloblastoma, one of the most prevalent childhood malignant brain tumors, were investigated to identify predisposing germline mutations. Initial findings were extended to genomes and epigenomes of 1,044 medulloblastoma cases from international multicenter cohorts, including retrospective and prospective clinical studies and patient series. We identified heterozygous germline mutations in the G protein-coupled receptor 161 ( ) gene in six patients with infant-onset medulloblastoma (median age, 1.5 years). mutations were exclusively associated with the sonic hedgehog medulloblastoma (MB ) subgroup and accounted for 5% of infant MB cases in our cohorts. Molecular tumor profiling revealed a loss of heterozygosity at in all affected MB tumors, atypical somatic copy number landscapes, and no additional somatic driver events. Analysis of 226 MB tumors revealed somatic copy-neutral loss of heterozygosity of chromosome 1q as the hallmark characteristic of deficiency and the primary mechanism for biallelic inactivation of in affected MB tumors. Here, we describe a novel brain tumor predisposition syndrome that is caused by germline mutations and characterized by MB in infants. Additional studies are needed to identify a potential broader tumor spectrum associated with germline mutations.