Methylation of the TERT promoter and risk stratification of childhood brain tumours: an integrative genomic and molecular study

Castelo‐Branco, Pedro; Choufani, Sanaa; Mack, Stephen C.; Gallagher, Denis; Zhang, Cindy; Lipman, Tatiana; Zhukova, Nataliya; Walker, Erin J.; Martin, Dianna C.; Merino, Diana M.; Wasserman, Jonathan D.; Elizabeth, Cynthia; Alon, Noa; Zhang, Libo; Hovestadt, Volker; Kool, Marcel; Jones, David; Zadeh, Gelareh; Croul, Sidney; Hawkins, Cynthia; Hitzler, Johann; Wang, Jean; Baruchel, Sylvain; Dirks, Peter B.; Malkin, David; Pfister, Stefan M.; Taylor, Michael D.; Weksberg, Rosanna; Tabori, Uri

doi:10.1016/s1470-2045(13)70110-4

Cited by 214 publications

(256 citation statements)

References 30 publications

Supporting

Mentioning

233

Contrasting

Unclassified

Order By: Relevance

“…[23][24][25] Together with the exceedingly low frequency of TERT promoter mutation identified in Figure 3 Kaplan-Meier survival analysis of IDH mutation, 1p/19q codeletion and TERT promoter mutation in lower-grade gliomas. Among all lower-grade gliomas analyzed, IDH mutation was associated with longer PFS (a) and OS (b), 1p/19q codeletion was associated with longer PFS (c) and OS (d), TERT promoter mutation was associated with longer OS (f) but not PFS (e).…”

Section: Discussionmentioning

confidence: 88%

TERT promoter mutations contribute to subset prognostication of lower-grade gliomas

Chan

Zhang

et al. 2015

Modern Pathology

View full text Add to dashboard Cite

Recurrent mutations in the promoter region of telomerase reverse transcriptase (TERT) have been found in various cancers including diffuse gliomas. Mutations lead to TERT upregulation and are associated with aggressive clinical behavior in glioblastomas. However, the clinical significance of TERT promoter mutations in lower-grade gliomas remains undetermined. The aim of this study is to evaluate the status of TERT promoter and the respective prognostic significance in a cohort of 237 lower-grade gliomas comprising grades II and III astrocytomas, oligodendrogliomas, and oligoastrocytomas. Mutually exclusive mutations in TERT promoter, C228T and C250T, were identified in 16/105 (15%) diffuse astrocytomas, 16/63 (25%) anaplastic astrocytomas, 13/18 (72%) oligodendrogliomas, 3/3 (100%) anaplastic oligodendrogliomas, 17/45 (38%) oligoastrocytomas, and 2/3 (67%) anaplastic oligoastrocytomas. Mutations co-occurred with 1p/19q codeletion (Po0.001) and are associated with oligodendroglial histology (Po0.001). Kaplan-Meier's survival analysis showed that TERT promoter mutation (P ¼ 0.037), Isocitrate dehydrogenase (IDH) mutation (Po0.001), and 1p/19q codeletion (Po0.001) were associated with favorable overall survival (OS). In the subset of 116 IDH-mutated lower-grade gliomas lacking 1p/19q codeletion, 19 TERT promoter-mutated tumors exhibited longer progression-free survival (PFS) (P ¼ 0.027) and OS (P ¼ 0.004). Consistent with this observation, in the subset of 97 IDH-mutated astrocytomas, 14 TERT promoter-mutated tumors showed longer PFS (P ¼ 0.001) and OS (P ¼ 0.001). In contrast, among the subset of 74 IDH wild-type lower-grade gliomas with intact 1p/19q, TERT promoter mutation was associated with shorter PFS (P ¼ 0.001) and OS (P ¼ 0.001). Similarly, in the subset of 65 IDH wild-type astrocytomas, 16 TERT promoter-mutated tumors exhibited unfavorable PFS (P ¼ 0.007) and OS (P ¼ 0.008). Our results indicate that when combined with IDH status, TERT promoter mutation contributes to prognostic subgroups of lower-grade astrocytic tumors or 1p/19q intact lower-grade gliomas and this may further refine future molecular classification of lower-grade gliomas.

show abstract

Section: Discussionmentioning

confidence: 88%

TERT promoter mutations contribute to subset prognostication of lower-grade gliomas

Chan

Zhang

et al. 2015

Modern Pathology

View full text Add to dashboard Cite

show abstract

“…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]. These findings are consistent with the fact that the cells, from which paediatric CNS tumours are thought to originate, still have activated telomerase which obviates the need for activation of TERT through promoter mutation.…”

Section: Telomerase Promoter Mutations In Bladder Carcinomasmentioning

confidence: 96%

Telomerase promoter mutations in cancer: an emerging molecular biomarker?

et al. 2014

View full text Add to dashboard Cite

Cell immortalization has been considered for a long time as a classic hallmark of cancer cells. Besides telomerase reactivation, such immortalization could be due to telomere maintenance through the "alternative mechanism of telomere lengthening" (ALT) but the mechanisms underlying both forms of reactivation remained elusive. Mutations in the coding region of telomerase gene are very rare in the cancer setting, despite being associated with some degenerative diseases. Recently, mutations in telomerase (TERT) gene promoter were found in sporadic and familial melanoma and subsequently in several cancer models, notably in gliomas, thyroid cancer and bladder cancer. The importance of these findings has been reinforced by the association of TERT mutations in some cancer types with tumour aggressiveness and patient survival. In the first part of this review, we summarize the data on the biology of telomeres and telomerase, available methodological approaches and nonneoplastic diseases associated with telomere dysfunction. In the second part, we review the information on telomerase expression and genetic alterations in the most relevant types of cancer (skin, thyroid, bladder and central nervous system) on record, and discuss the value of telomerase as a new biomarker with impact on the prognosis and survival of the patients and as a putative therapeutic target.

show abstract

“…Christian Koelsche 1,2 , Felix Sahm , Wolfgang Wick 5,6 , Andrey Korshunov 1,2 and Andreas von Deimling…”

Section: Distribution Of Tert Promoter Mutations In Pediatric and Aduunclassified

“…Single nucleotide polymorphisms in the TERT gene have been associated with telomere length and have been associated with risk for breast and ovarian cancer [3]. Also the methylation status of distinct CpG sites in the TERT promoter has been associated with TERT expression, tumor progression and poor prognosis in pediatric nervous system tumors [5]. The most frequent alteration in the TERT gene, somatic promoter mutations, have been described in melanoma [9,12,13], primary nervous system tumors [2,14,17,23,30], thyroid [15,16], hepatocellular carcinomas [21] and bladder [17] as well as many other tumor types [14,30].…”

Section: Introductionmentioning

confidence: 99%

Distribution of TERT promoter mutations in pediatric and adult tumors of the nervous system

et al. 2013

Self Cite

View full text Add to dashboard Cite

Hot spot mutations in the promoter region of telomerase reverse transcriptase (TERT) have recently been described in several human tumor entities. These mutations result in an upregulation of the telomerase complex activity and thus constitute a relevant mechanism for immortalization of tumor cells. Knowledge of the TERT promoter status in tumors is likely to be of interest for molecular classification and as a potential target for therapy. We, therefore, performed a systematic analysis of TERT promoter mutations in 1,515 tumors of the human nervous system and its coverings including 373 pediatric and 1,142 adult patients. We detected a total of 327 mutations. TERT promoter mutations were exceedingly rare in tumors typically encountered in pediatric patients. In entities typically encountered in adult patients TERT promoter mutations were strongly associated with older age (p < 0.0001). Highest mutation frequencies were detected in gliosarcomas (81 %), oligodendrogliomas (78 %), oligoastrocytomas (58 %), primary glioblastomas (54 %), and solitary fibrous tumors (50 %). Related to other molecular alterations, TERT promoter mutations were strongly associated with 1p/19q loss (p < 0.0001), but inversely associated with loss of ATRX expression (p < 0.0001) and IDH1/IDH2 mutations (p < 0.0001). TERT promoter mutations are typically found in adult patients and occur in a highly tumor typeassociated distribution. classification and as a potential target for therapy. We, therefore, performed a systematic analysis of TERT promoter mutations in 1515 tumors of the human nervous system and its coverings including 373 pediatric and 1142 adult patients. We detected a total of 327 mutations. TERT promoter mutations were exceedingly rare in tumors typically encountered in pediatric patients. In entities typically encountered in adult patients TERT promoter mutations were strongly associated with older age (p < 0.0001). Highest mutation frequencies were detected in gliosarcomas (81 %), oligodendrogliomas (78 %), oligoastrocytomas (58 %), primary glioblastomas (54 %) and solitary fibrous tumors (50 %).Related to other molecular alterations, TERT promoter mutations were strongly associated with 1p/19q loss (p < 0.0001), but inversely associated with loss of ATRX expression (p < 0.0001) and IDH1/IDH2

show abstract

Methylation of the TERT promoter and risk stratification of childhood brain tumours: an integrative genomic and molecular study

Cited by 214 publications

References 30 publications

TERT promoter mutations contribute to subset prognostication of lower-grade gliomas

TERT promoter mutations contribute to subset prognostication of lower-grade gliomas

Telomerase promoter mutations in cancer: an emerging molecular biomarker?

Distribution of TERT promoter mutations in pediatric and adult tumors of the nervous system

Contact Info

Product

Resources

About