Abstract
Telomerase reverse transcriptase (TERT) promoter mutations were recently shown to drive telomerase activity in various cancer types, including medulloblastoma. However, the clinical and biological implications of TERT mutations in medulloblastoma have not been described. Hence, we sought to describe these mutations and their impact in a subgroup-specific manner. We analyzed the TERT promoter by direct sequencing and genotyping in 466 medulloblastomas. The mutational distributions were determined according to subgroup affiliation, demographics, and clinical, prognostic, and molecular features. Integrated genomics approaches were used to identify specific somatic copy number alterations in TERT promoter-mutated and wild-type tumors. Overall, TERT promoter mutations were identified in 21 % of medulloblastomas. Strikingly, the highest frequencies of TERT mutations were observed in SHH (83 %; 55/66) and WNT (31 %; 4/13) medulloblastomas derived from adult patients. Group 3 and Group 4 harbored this alteration in <5 % of cases and showed no association with increased patient age. The prognostic implications of these mutations were highly subgroup-specific. TERT mutations identified a subset with good and poor prognosis in SHH and Group 4 tumors, respectively. Monosomy 6 was mostly restricted to WNT tumors without TERT mutations. Hallmark SHH focal copy number aberrations and chromosome 10q deletion were mutually exclusive with TERT mutations within SHH tumors. TERT promoter mutations are the most common recurrent somatic point mutation in medulloblastoma, and are very highly enriched in adult SHH and WNT tumors. TERT mutations define a subset of SHH medulloblastoma with distinct demographics, cytogenetics, and outcomes.Electronic supplementary materialThe online version of this article (doi:10.1007/s00401-013-1198-2) contains supplementary material, which is available to authorized users.
Highlights
Medulloblastoma is a highly malignant embryonal brain tumor located in the posterior fossa [6, 29, 33, 35]
We demonstrate that Telomerase reverse transcriptase (TERT) promoter mutations comprise the most recurrent mutation in adult SHH tumors identified to date and potentially define distinct prognostic subgroups in SHH and Group 4 medulloblastoma patients
Next-generation sequencing studies have revealed a broad spectrum of novel, potentially tumorigenic mutations in the recent past, but none of these studies focused on adult medulloblastomas [12, 25, 32, 34, 39]
Summary
Medulloblastoma is a highly malignant embryonal brain tumor located in the posterior fossa [6, 29, 33, 35]. While this tumor comprises the most common malignant brain tumor in children, it only accounts for approximately 1 % of primary CNS tumors in adults [18, 20]. The current consensus recognizes four core molecular subgroups (WNT, SHH, Group 3, and Group 4) with distinct molecular, demographic, clinicopathological, and prognostic characteristics [5, 15, 16, 26, 27, 37, 38, 41, 42].
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