DNA methylation profiling of medulloblastoma allows robust subclassification and improved outcome prediction using formalin-fixed biopsies

Schwalbe, Ed C.; Williamson, Daniel; Lindsey, John H.; Hamilton, Dolores Mary; Ryan, Sarra; Megahed, Hisham; Garami, Miklós; Hauser, Péter; Dembowska‐Bagińska, Bożenna; Perek, Danuta; Northcott, Paul A.; Taylor, Michael D.; Taylor, Roger; Ellison, David W.; Bailey, Simon; Clifford, Steven C.

doi:10.1007/s00401-012-1077-2

Cited by 142 publications

(144 citation statements)

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“…Analysis of localized hypomethylated regions further revealed an interesting link between these regions and binding of transcription factors that might be responsible for subgroup-specific signature gene expression and tumorigenesis (99). Methylation analysis not only has provided insight into the mechanisms of altered gene expression in MB but also has become an important tool for subgrouping and risk stratification (107), complementing the widely used genetic profiling approaches (8). Further studies will be necessary to understand the interplay between epigenetic and genetic events, and the functional significance of these alterations in tumorigenesis (95).…”

Section: Epigenetic Regulation In Mbmentioning

confidence: 99%

Molecular mechanisms and therapeutic targets in pediatric brain tumors

et al. 2017

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Brain tumors are among the leading causes of cancer-related deaths in children. Although surgery, aggressive radiation, and chemotherapy have improved outcomes, many patients still die of their disease. Moreover, those who survive often suffer devastating long-term side effects from the therapies. A greater understanding of the molecular underpinnings of these diseases will drive the development of new therapeutic approaches. Advances in genomics and epigenomics have provided unprecedented insight into the molecular diversity of these diseases and, in several cases, have revealed key genes and signaling pathways that drive tumor growth. These not only serve as potential therapeutic targets but also have facilitated the creation of animal models that faithfully recapitulate the human disease for preclinical studies. In this Review, we discuss recent progress in understanding the molecular basis of the three most common malignant pediatric brain tumors-medulloblastoma, ependymoma, and high-grade glioma-and the implications for development of safer and more effective therapies.

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Section: Epigenetic Regulation In Mbmentioning

confidence: 99%

Molecular mechanisms and therapeutic targets in pediatric brain tumors

et al. 2017

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“…of TERT mutations in medulloblastoma subgroups (subgroups determined as previously described [4,10]). Mutations were frequently and exclusively detected in the non-infant MB SHH subgroups (X 2 test between MB SHH age groups shown).…”

Section: Supplementary Materialsmentioning

confidence: 99%

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

et al. 2013

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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...

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“…It is still motivating to find further prognostic markers [3,6,11,23,25,27,34]. Nowadays, an exact diagnosis of pediatric brain tumors can be established based on the methylation profile of dif- [18,21,35]. DNMTs are responsible for DNA methylation, an important epigenetic regulation process, which contributes to development of cancer.…”

Section: Discussionmentioning

confidence: 99%

“…Recent studies indicate that the DNA methylation profile can be used for MB subgrouping and disease risk assessment [18,35].…”

Section: Introductionmentioning

confidence: 99%