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Germline GPR161 mutations predispose to pediatric medulloblastoma

PURPOSEThe 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.METHODSFamilies with childhood medulloblastoma, one o...

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Main Authors: Begemann, Matthias (Author) , Waszak, Sebastian M. (Author) , Robinson, Giles W. (Author) , Jäger, Natalie (Author) , Sharma, Tanvi (Author) , Knopp, Cordula (Author) , Kraft, Florian (Author) , Moser, Olga (Author) , Mynarek, Martin (Author) , Guerrini-Rousseau, Lea (Author) , Brugieres, Laurence (Author) , Varlet, Pascale (Author) , Pietsch, Torsten (Author) , Bowers, Daniel C. (Author) , Chintagumpala, Murali (Author) , Sahm, Felix (Author) , Korbel, Jan Oliver (Author) , Rutkowski, Stefan (Author) , Eggermann, Thomas (Author) , Gajjar, Amar (Author) , Northcott, Paul (Author) , Elbracht, Miriam (Author) , Pfister, Stefan (Author) , Kontny, Udo (Author) , Kurth, Ingo (Author)
Format: Article (Journal)
Language:English
Published: October 14, 2019
In: Journal of clinical oncology
Year: 2019, Volume: 38, Issue: 1, Pages: 43-50
ISSN:1527-7755
DOI:10.1200/JCO.19.00577
Online Access:Verlag, lizenzpflichtig, Volltext: https://doi.org/10.1200/JCO.19.00577
Verlag, lizenzpflichtig, Volltext: https://ascopubs.org/doi/10.1200/JCO.19.00577
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Author Notes:Matthias Begemann, PhD; Sebastian M. Waszak, PhD; Giles W. Robinson, MD; Natalie Jäger, PhD; Tanvi Sharma, MSc; Cordula Knopp, MD; Florian Kraft, PhD; Olga Moser, MD; Martin Mynarek, MD; Lea Guerrini-Rousseau, MD; Laurence Brugieres, MD; Pascale Varlet, MD, PhD; Torsten Pietsch, MD; Daniel C. Bowers, MD; Murali Chintagumpala, MD; Felix Sahm, MD; Jan O. Korbel, PhD; Stefan Rutkowski, MD; Thomas Eggermann, PhD; Amar Gajjar, MD; Paul Northcott, PhD; Miriam Elbracht, MD; Stefan M. Pfister, MD; Udo Kontny, MD; and Ingo Kurth MD
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Summary:PURPOSEThe 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.METHODSFamilies 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.RESULTSWe 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.CONCLUSIONHere, 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.
Item Description:Gesehen am 15.04.2020
Physical Description:Online Resource
ISSN:1527-7755
DOI:10.1200/JCO.19.00577

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