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

Abstract

The childhood brain tumour medulloblastoma comprises four molecular disease subgroups (MB WNT , MB SHH , MB Group3 and MB Group4 ). However, large-scale whole-exome sequencing investigations have not identified defining genetic lesions for the non-MB WNT subgroups [8,11]. Recent studies reported in this journal and others [1,3,6,7,9] have identified frequent TERT promoter mutations and aberrant DNA methylation in CNS malignancies, suggesting an important mechanism in tumour development ( Figure 1a). In medulloblastoma, reported a high frequency of TERT promoter methylation, while Killela et al. [6] described TERT promoter mutations which Koelsche et al.[7] and Remke et al. [9] subsequently reported were most frequent in adult MB SHH , but rarer in childhood 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. Notably, in the non-infant MB SHH patient group aged 4 and over at diagnosis within our cohort, we show these genetic and epigenetic aberrations occur in both childhood and adult tumours, and in a mutually exclusive fashion, representing a defining molecular alteration in >75% of this patient group. TERT promoter mutations occurred at high frequency in both childhood (14/41 (34%)) and adult (8/11 (73%)) MB SHH (Figure 1b) in our cohort, more common than any coding mutation reported in these groups to date (TP53, 30%; PTCH1, 27%; DDX3X, 18%; all other genes, <6% (n=33, data from cancer.sanger.ac.uk). The age distributions of mutated (4.7-15.5 years) and non-mutated (5.2-15.4 years) childhood patients did not differ significantly (p=0.27; Mann-Whitney U test). TERT mutations were tumour-specific where germline DNA was available for comparison (n=4) and exclusive to non-infant MB SHH in our investigations. Mutations were not found in MB WNT (n=16; age range, 4.7-16.8 years), MB Group3 (n=16; 1.5-16.1 years) or MB Group4 (n=20; 2.4-15.8 years) from infants and children, or in tumours from infant MB SHH (<4.0 at diagnosis; n=17; 0.2-3.5 years), consistent with the rarity of mutations in these subgroups reported by Remke et al. [9] Aberrant TERT promoter methylation at cg...

Allele-Specific DNA Methylation and Its Interplay with Repressive Histone Marks at Promoter-Mutant TERT Genes

“…Thus, the machinery maintaining the immortal phenotype in these two classes of cancers is distinct. Reduced 5mC in the TERT promoter has been reported previously for isolated subtypes of cancers with −124 mutations (Fan et al, 2016; Lindsey et al, 2014), although the allele specificity of 5mC has not previously been reported. Our analyses of large datasets of clinical samples broaden these findings to numerous cancers across many tissue types and provide a mechanistic rationale for how DNA methylation may effect TERT gene silencing in −124 cancers.…”

The role of histone modifications and telomere alterations in the pathogenesis of diffuse gliomas in adults and children

“…Although pediatric TERT promoter mutations are rare, a single study has reported TERT promoter hypermethylation in association with increased TERT expression in pediatric high-grade gliomas [50]. Aberrant TERT promoter methylation with increased TERT expression has been reported in other cancer types [51, 52, 53]. In adult gliomas TERT promoter mutation rather than promoter methylation is the predominant mechanism for TERT upregulation [54].…”

Genetic and Epigenetic Alterations of TERT Are Associated with Inferior Outcome in Adolescent and Young Adult Patients with Melanoma

“…showed that coexistence of TERT promoter and BRAF or NRAS mutations was associated with a 2-fold reduced rate of disease-free survival and a 5-fold reduced rate of melanoma-specific survival in patients with stage I and II melanoma26. TERT promoter hypermethylation is also an effective molecular marker for prognosis in a number of cancer types, and was previously shown to correlate with increased TERT expression in a subset of melanomas2933373839.…”