Published in:
01-02-2014 | Correspondence
TERT promoter mutation and aberrant hypermethylation are associated with elevated expression in medulloblastoma and characterise the majority of non-infant SHH subgroup tumours
Published in: Acta Neuropathologica | Issue 2/2014
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The childhood brain tumour medulloblastoma comprises four molecular disease subgroups (MBWNT, MBSHH, MBGroup3 and MBGroup4). However, large-scale whole-exome sequencing investigations have not identified defining genetic lesions for the non-MBWNT 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 (Fig. 1a). In medulloblastoma, Castelo-Branco et al. [3] 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 MBSHH, 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 MBSHH, 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 Castelo-Branco et al. [3] is contradicted by the inverse association described by Arita et al. [1] in TERT wild-type adult gliomas.
Fig. 1
TERT non-coding mutations, aberrant DNA hypermethylation, and expression in medulloblastoma. a The TERT promoter region, showing positions of mutational hotspots and methylated regulatory CpG site, relative to the translational start site. b Numbers and frequencies (%) of TERT mutations in medulloblastoma subgroups (subgroups determined as previously described [4, 10]). Mutations were frequently and exclusively detected in the non-infant MBSHH subgroups (χ 2 test between MBSHH age groups shown). The three different mutations are colour coded (pink, purple and gold). c TERT promoter CpG site cg11625005 DNA methylation levels (β-value, assessed by Illumina Human Methylation 450 K array [2]), are shown for normal cerebella (grey), MBSHH (by age; red), MBWNT (blue), MBGroup3 (yellow), and MBGroup4 (green). Black horizontal line, upper 99 % confidence interval of mean cerebellar methylation levels, above which tumours were classed as aberrantly hypermethylated. ‘p’ value, one-way analysis of variance between tumour groups shown. d TERT promoter methylation in MBSHH tumours from patients ≥4 years old at diagnosis. CpG site cg11625005 DNA methylation levels (β-value) are shown for TERT mutated (n = 10) and wild-type non-infant MBSHH (n = 17) and normal cerebella (n = 17, grey). Specific mutations are colour coded as above (b). The mean methylation level was significantly higher in wild-type tumours compared to either mutated tumours (p = 0.0006) or the normal cerebellum (p = 0.00001) (Student’s t test). Black horizontal line, see above (c). e TERT expression (by RNA-seq; further details given in Supplementary Table 1) vs. TERT promoter CpG site cg11625005 DNA methylation levels and mutation status in 51 medulloblastomas. Subgroup assignment is coloured as above (c). Mutated tumours, bold outlined boxes; wild-type tumours, circles. Dashed line, linear regression of methylation vs. expression in TERT wild-type tumours with associated ‘p’ values (Pearson’s correlation). VSD, variance-stabilised transform of normalised read counts aligned to ENSG00000164362. All tumour-specific data are summarised in Supplementary Table 1
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