Germline mutations in GPR161, encoding a Sonic Hedgehog regulator, predispose to medulloblastoma.

  • Major Finding: Germline mutations in GPR161, encoding a Sonic Hedgehog regulator, predispose to medulloblastoma.

  • Mechanism: Copy-number loss of heterozygosity of GPR161 underlies the development of infant medulloblastoma.

  • Impact: This study identifies a previously unknown Sonic Hedgehog medulloblastoma risk syndrome.

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Medulloblastomas most often appear to occur sporadically, but heritable causes have been identified in some cases. Begemann, Waszak, and colleagues describe a previously unknown medulloblastoma predisposition syndrome caused by heterozygous germline mutations in GPR161, a gene encoding a G protein-coupled receptor that regulates Sonic Hedgehog (SHH). The index patient had developed TP53WT SHH medulloblastoma (SHH-MB) at the age of 12 months and subsequently developed tumors of several other types. Analysis of genomic data from a 1,044-patient medulloblastoma cohort identified five additional patients with mutations in GPR161, all of whom had developed SHH-MB at a young age, with a median age of onset of 1.5 years. None of these six patients had mutations previously known to drive medulloblastoma. In five of the six patients, loss of the wild-type copy of GPR161 had occurred as a result of 1q copy-number neutral loss of heterozygosity (cnLOH), a genetic alteration that had not previously been associated with medulloblastoma. An analysis of genomic data from patients with pediatric SHH-MB revealed that 1q cnLOH was only present in tumors harboring germline GPR161 mutations. In total, the authors estimate that 5% of infant SHH-MBs are attributable to GPR161 mutations. Heterozygosity for these mutations is rare in the general population; the carrier frequency is approximately 1 in 42,000 to 1 in 125,000 individuals. In summary, this study identifies a previously unknown medulloblastoma predisposition syndrome, providing information that not only will enable genetic counseling for carriers but also may yield insights into underlying processes that can drive medulloblastoma in patients without the mutation.

Begemann M, Waszak SM, Robinson GW, Jäger N, Sharma T, Knopp C, et al. Germline GPR161 mutations predispose to pediatric medulloblastoma. J Clin Oncol 2019 Oct 14 [Epub ahead of print].

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