Germline GPR161 Mutations Predispose to Pediatric Medulloblastoma

Abstract

Purpose: 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.

Methods: 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.

Results: We identified heterozygous germline mutations in the G protein-coupled receptor 161 (GPR161) gene in six patients with infant-onset medulloblastoma (median age, 1.5 years). GPR161 mutations were exclusively associated with the sonic hedgehog medulloblastoma (MB_SHH) subgroup and accounted for 5% of infant MB_SHH cases in our cohorts. Molecular tumor profiling revealed a loss of heterozygosity at GPR161 in all affected MB_SHH tumors, atypical somatic copy number landscapes, and no additional somatic driver events. Analysis of 226 MB_SHH tumors revealed somatic copy-neutral loss of heterozygosity of chromosome 1q as the hallmark characteristic of GPR161 deficiency and the primary mechanism for biallelic inactivation of GPR161 in affected MB_SHH tumors.

Conclusion: Here, we describe a novel brain tumor predisposition syndrome that is caused by germline GPR161 mutations and characterized by MB_SHH in infants. Additional studies are needed to identify a potential broader tumor spectrum associated with germline GPR161 mutations.

FIG 1.

Index patient with medulloblastoma and germline GPR161 mutation. (A) Desmoplastic/nodular medulloblastoma, SHH-activated, TP53 wild type (WHO grade IV) in the index case (M20769). Highly cellular, undifferentiated small-cell neoplasm with increased mitotic activity. Silver impregnation shows an increased density of argyric fibers. The cells express the neural marker MAP2 and the SHH target protein p75-NGFR. (B) Index patient (27 years old). (C) Pedigree of the index patient (gray) with MB (black arrow). Father (red) was carrier of the GPR161 germline mutation and died from colorectal cancer. Asymptomatic GPR161 mutation carriers are indicated in purple. (D) Sanger sequencing-based validation of the germline GPR161 frameshift mutation (c.547_548delCT) in peripheral blood (upper panel) and medulloblastoma (lower panel) of the index case. (E) Loss of heterozygosity analysis of chromosome 1 based on targeted gene panel sequencing of tumor DNA. GPR161 location is highlighted with an arrow.

FIG 2.

Genomic landscape of GPR161-associated medulloblastoma. (A) Germline GPR161 mutations in patients with MB. (B) Demographic and molecular characteristics of GPR161-associated MB. (C) Age at diagnosis across pediatric patients with pathogenic germline mutations in MB_SHH predisposition genes. (D) Frequency of pathogenic germline mutations in pediatric MB_SHH. (E) Frequency of germline GPR161 mutations in retrospective and prospective pediatric MB_SHH cohorts. (F) Frequency of somatic 1p/1q LOH events in MB_SHH tumors and association between 1q LOH and GPR161 mutation status. LOH, loss of heterozygosity; MB, medulloblastoma; Mut, mutant; SHH, sonic hedgehog; WT, wild type.