@article{1d354ed45a2a4efe85a5d0a4c70fc998,
title = "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 (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. CONCLUSION 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.",
keywords = "Brain Neoplasms/genetics, Child, Child, Preschool, Cohort Studies, DNA Methylation, Female, Genetic Predisposition to Disease, Germ-Line Mutation, Hedgehog Proteins/genetics, Heterozygote, Humans, Infant, Medulloblastoma/genetics, Prospective Studies, Receptors, G-Protein-Coupled/genetics, Signal Transduction, Whole Exome Sequencing",
author = "Matthias Begemann and Waszak, {Sebastian M.} and Robinson, {Giles W.} and Natalie J{\"a}ger and Tanvi Sharma and Cordula Knopp and Florian Kraft and Olga Moser and Martin Mynarek and Lea Guerrini-Rousseau and Laurence Brugieres and Pascale Varlet and Torsten Pietsch and Bowers, {Daniel C.} and Murali Chintagumpala and Felix Sahm and Korbel, {Jan O.} and Stefan Rutkowski and Thomas Eggermann and Amar Gajjar and Paul Northcott and Miriam Elbracht and Pfister, {Stefan M.} and Udo Kontny and Ingo Kurth",
note = "Funding Information: Supported by Deutsche Forschungsgemeinschaft Grants No. EG110/15-1 and 948/32-1 FUGG; partially funded by the PedBrain Tumor Project contributing to the International Cancer Genome Consortium, Grant No. 109252 from German Cancer Aid, and Grants No. 01KU1201A and 01KU1201C from the German Federal Ministry of Education and Research. Additional funding through German Federal Ministry of Education and Research BioTop Grants No. 01EK1502A and 01EK1502B and International Cancer Genome Consortium Data Mining (Grant No. 01KU1505F), Grant No. 111234 from the German Cancer Aid, and Grant No. A2013/46 DKS2014.12 from the German Childhood Cancer Foundation (Deutsche Kinderkrebsstiftung). The Hirntumor-Studiengruppe f{\"u}r Medulloblastome study group and the Deutsche Gesellschaft f{\"u}r Neuropathologie und Neuroanatomie Brain Tumor Reference Center are supported by the German Childhood Cancer Foundation (Deutsche Kinderkrebsstiftung). S.M.W. received funding through a Swiss National Science Foundation early postdoctoral mobility fellowship (P2ELP3_155365) and a European Molecular Biology Organization Long-Term Fellowship (ALTF 755-2014). J.O.K. is Funding Information: The authors acknowledge the Next Generation Sequencing Diagnostic Center Aachen and the Comprehensive Diagnostic Center Aachen. The authors thank Christina Backhaus, Elvira Golz-Staggemeyer, Hai Yen Nguyen, and Laura D{\"o}rner for excellent technical assistance. The authors also thank the Genomics and Proteomics Core Facility at the German Cancer Research Centre (Stephan Wolf and team) for performing whole-exome sequencing and the Microarray Core Facility at the German Cancer Research Centre (Melanie Bewerunge-Hudler and team) for performing DNA methylation analysis. Publisher Copyright: {\textcopyright} 2019 by American Society of Clinical Oncology",
year = "2020",
month = jan,
day = "1",
doi = "10.1200/JCO.19.00577",
language = "English (US)",
volume = "38",
pages = "43--50",
journal = "Journal of Clinical Oncology",
issn = "0732-183X",
publisher = "Wolters Kluwer",
number = "1",
}