Germline GPR161 Mutations Predispose to Pediatric Medulloblastoma.

Journal of clinical oncology : official journal of the American Society of Clinical Oncology 2020 Jan 01

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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 (GPR161) gene in six patients with infant-onset medulloblastoma (median age, 1.5 years). GPR161 mutations were exclusively associated with the sonic hedgehog medulloblastoma (MBSHH) subgroup and accounted for 5% of infant MBSHH cases in our cohorts. Molecular tumor profiling revealed a loss of heterozygosity at GPR161 in all affected MBSHH tumors, atypical somatic copy number landscapes, and no additional somatic driver events. Analysis of 226 MBSHH 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 MBSHH tumors. Here, we describe a novel brain tumor predisposition syndrome that is caused by germline GPR161 mutations and characterized by MBSHH in infants. Additional studies are needed to identify a potential broader tumor spectrum associated with germline GPR161 mutations.

Citation

Matthias Begemann, Sebastian M Waszak, Giles W Robinson, Natalie Jäger, Tanvi Sharma, Cordula Knopp, Florian Kraft, Olga Moser, Martin Mynarek, Lea Guerrini-Rousseau, Laurence Brugieres, Pascale Varlet, Torsten Pietsch, Daniel C Bowers, Murali Chintagumpala, Felix Sahm, Jan O Korbel, Stefan Rutkowski, Thomas Eggermann, Amar Gajjar, Paul Northcott, Miriam Elbracht, Stefan M Pfister, Udo Kontny, Ingo Kurth. Germline GPR161 Mutations Predispose to Pediatric Medulloblastoma. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2020 Jan 01;38(1):43-50