5 research outputs found
Telomerase inhibition abolishes the tumorigenicity of pediatric ependymoma tumor-initiating cells
Pediatric ependymomas are highly recurrent tumors resistant to conventional chemotherapy. Telomerase, a ribonucleoprotein critical in permitting limitless replication, has been found to be critically important for the maintenance of tumor-initiating cells (TICs). These TICs are chemoresistant, repopulate the tumor from which they are identified, and are drivers of recurrence in numerous cancers. In this study, telomerase enzymatic activity was directly measured and inhibited to assess the therapeutic potential of targeting telomerase. Telomerase repeat amplification protocol (TRAP) (n = 36) and C-circle assay/telomere FISH/ATRX staining (n = 76) were performed on primary ependymomas to determine the prevalence and prognostic potential of telomerase activity or alternative lengthening of telomeres (ALT) as telomere maintenance mechanisms, respectively. Imetelstat, a phase 2 telomerase inhibitor, was used to elucidate the effect of telomerase inhibition on proliferation and tumorigenicity in established cell lines (BXD-1425EPN, R254), a primary TIC line (E520) and xenograft models of pediatric ependymoma. Over 60 % of pediatric ependymomas were found to rely on telomerase activity to maintain telomeres, while no ependymomas showed evidence of ALT. Children with telomerase-active tumors had reduced 5-year progression-free survival (29 +/- A 11 vs 64 +/- A 18 %; p = 0.03) and overall survival (58 +/- A 12 vs 83 +/- A 15 %; p = 0.05) rates compared to those with tumors lacking telomerase activity. Imetelstat inhibited proliferation and self-renewal by shortening telomeres and inducing senescence in vitro. In vivo, Imetelstat significantly reduced subcutaneous xenograft growth by 40 % (p = 0.03) and completely abolished the tumorigenicity of pediatric ependymoma TICs in an orthotopic xenograft model. Telomerase inhibition represents a promising therapeutic approach for telomerase-active pediatric ependymomas found to characterize high-risk ependymomas.Canadian Institutes of Health Research [MOP 82727]info:eu-repo/semantics/publishedVersio
TERT promoter mutations are highly recurrent in SHH subgroup medulloblastoma
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 wit
Driver mutations in histone H3.3 and chromatin remodelling genes in paediatric glioblastoma
Glioblastoma multiforme (GBM) is a lethal brain tumour in adults
and children. However, DNA copy number and gene expression
signatures indicate differences between adult and paediatric cases1–4.
To explore the genetic events underlying this distinction, we
sequenced the exomes of 48 paediatricGBMsamples.Somaticmutations
in the H3.3-ATRX-DAXX chromatin remodelling pathway
were identified in 44% of tumours (21/48). Recurrent mutations
in H3F3A, which encodes the replication-independent histone 3
variant H3.3, were observed in 31% of tumours, and led to amino
acid substitutions at two critical positions within the histone tail
(K27M, G34R/G34V) involved in key regulatory post-translational
modifications.Mutations inATRX (a-thalassaemia/mental retardation
syndrome X-linked)5 and DAXX (death-domain associated
protein), encoding two subunits of a chromatin remodelling
complex required for H3.3 incorporation at pericentric heterochromatin
and telomeres6,7, were identified in 31% of samples overall,
and in 100% of tumours harbouring a G34R or G34V H3.3 mutation.
Somatic TP53 mutations were identified in 54% of all cases,
and in 86% of samples with H3F3A and/or ATRX mutations.
Screening of a large cohort of gliomas of various grades and
histologies (n5784) showedH3F3A mutations to be specific toGBM
and highly prevalent in children and young adults. Furthermore,
the presence of H3F3A/ATRX-DAXX/TP53 mutations was
strongly associated with alternative lengthening of telomeres and
specific gene expression profiles. This is, to our knowledge, the first
report to highlight recurrent mutations in a regulatory histone in
humans, and our data suggest that defects of the chromatin architecture
underlie paediatric and young adult GBM pathogenesis