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.

Fig. 1

TERT promoter-mutated medulloblastomas display distinct demographics, histology, and subgroup affiliation. a Bar graph indicating the frequency of TERT mutations in 466 primary medulloblastomas. b Prevalence of TERT mutations according to medulloblastoma subgroups, and within, c WNT and d SHH subgroups according to age groups. Distribution of histological variants within SHH tumors according to TERT mutational status (e). MUT mutation, OS overall survival, WT wild-type

Fig. 2

Prognostic impact of TERT promoter mutations varies according to medulloblastoma subgroups. Kaplan–Meier estimate displaying overall survival (OS) according to TERT mutational status in primary medulloblastomas (a), within WNT (b), SHH (c), and Group 4 (d) subgroups. Survival differences were calculated using continuous log-rank tests. MUT mutation, OS overall survival, WT wild-type

Fig. 3

TERT promoter mutations delineate prognostic subsets within non-infant SHH and Group 4 medulloblastomas. Kaplan–Meier estimate displaying overall survival (OS) in non-infant medulloblastomas (>3 years of age at diagnosis) according to TERT mutational status across subgroups (a), in SHH tumors (b), in SHH tumors (TP53 mutated/wild-type) (c), and Group 4 (d). Survival differences were calculated using continuous log-rank tests

Fig. 4

WNT and SHH medulloblastoma harbor distinct broad genomic imbalances depending on the mutational status of TERT. Bar graphs indicating the frequency of broad cytogenetic alterations in WNT (a), and SHH (b) tumors. ★★ p < 0.01; ★ p < 0.05; MUT mutation, WT wild-type

Fig. 5

Focal somatic copy number alterations are largely confined to TERT wild-type SHH medulloblastomas. GISTIC2 analysis indicating focal amplifications/deletions in 108 wild-type (a, c) and 64 mutant (b, d) SHH tumors, respectively. Star regions enriched for reported DNA copy number variations