In:
Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 38, No. 1 ( 2020-01-01), p. 43-50
Abstract:
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.
Type of Medium:
Online Resource
ISSN:
0732-183X
,
1527-7755
DOI:
10.1200/JCO.19.00577
Language:
English
Publisher:
American Society of Clinical Oncology (ASCO)
Publication Date:
2020
detail.hit.zdb_id:
2005181-5
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