TERT promoter mutations are highly recurrent in SHH subgroup medulloblastoma

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.

Telomerase reverse transcriptase promoter mutations in tumors originating from the adrenal gland and extra-adrenal paraganglia

“…In this study, TERT promoter mutations were not detected in any peripheral neuroblastic tumor being consistent with the data stemming from a recent whole-genome sequencing project for NBLs (Molenaar et al 2012) and similar observations concerning other pediatric embryonal tumors, such as a clinically distinct molecular subtype of medulloblastoma (Killela et al 2013, Remke et al 2013. Nevertheless, three human NBL cell lines harbored TERT promoter mutations indicating that lack in tumor samples could be attributed either to decreased sensitivity of the technique owing to the presence of normal cells or to the inclusion of other peripheral neuroblastic tumor types, such as ganglioneuroblastomas and/or ganglioneuromas.…”

Telomerase promoter mutations in cancer: an emerging molecular biomarker?

“…TERT promoter mutations are rare in paediatric tumours of the CNS [63]. In medulloblastomas that typically develop in children, TERT promoter mutations are mainly detected in tumours of the group of older patients and are associated with sonic hedgehog and WNT mutations [102]. Upregulation of TERT expression in paediatric brain tumours was associated with hypermethylation of the TERT promoter, rather than with TERT promoter mutations [19].…”

TERT promoter mutation and aberrant hypermethylation are associated with elevated expression in medulloblastoma and characterise the majority of non-infant SHH subgroup tumours

“…However, while TERT mutations have been associated with elevated expression in other cancers [1,5], and account for a proportion of MB SHH , the relative contribution of TERT methylation alterations has not yet been investigated alongside mutational analysis. Moreover, relationships between TERT promoter methylation and gene expression are unclear; the positive association reported across multiple malignancies by is contradicted by the inverse association described by Arita et al [1] in TERT wild-type adult gliomas.We therefore sought to clarify the role of TERT alterations in medulloblastoma, by assessing the frequency of TERT promoter hot-spot mutations [1,6,7,9], aberrant methylation of the critical cg11625005 TERT promoter CpG residue [3], and TERT expression, in our tumour series. We show a common, subgroup-specific, involvement of TERT mutations in MB SHH alongside a wider involvement of TERT methylation across the MB subgroups, both associated with elevated TERT expression.…”