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Telomere length and Wnt/β-catenin pathway in adamantinomatous craniopharyngiomas
in European Journal of Endocrinology*(J I S Mota and R M P Silva-Júnior contributed equally to this work)
†(R M P Silva-Júnior is now at Institute of Neuroscience of Castilla y León, University of Salamanca, Salamanca, Spain)
‡(C S Martins is now at Faculty of Medicine, Federal University of Mato Grosso do Sul, Campo Grande, Brazil)
§(J G O Ozaki is now at Sonimed Medicina Diagnóstica, Campo Grande, Brazil)
Objectives
To evaluate how telomere length behaves in adamantinomtous craniopharyngioma (aCP) and if it contributes to the pathogenesis of aCPs with and without CTNNB1 mutations.
Design
Retrospective cross-sectional study enrolling 42 aCP patients from 2 tertiary institutions.
Methods
Clinicopathological features were retrieved from the patient’s charts. Fresh frozen tumors were used for RNA and DNA analyses. Telomere length was evaluated by qPCR (T/S ratio). Somatic mutations in TERT promoter (TERTp) and CTNNB1 were detected by Sanger and/or whole-exome sequencing. We performed RNA-Seq to identify differentially expressed genes in aCPs presenting with shorter or longer telomere lengths.
Results
Mutations in CTNNB1 were detected in 29 (69%) tumors. There was higher frequency of CTNNB1 mutations in aCPs from patients diagnosed under the age of 15 years (85% vs 15%; P = 0.04) and a trend to recurrent disease (76% vs 24%; P = 0.1). No mutation was detected in the TERTp region. The telomeres were shorter in CTNNB1-mutated aCPs (0.441, IQR: 0.297–0.597vs 0.607, IQR: 0.445–0.778; P = 0.04), but it was neither associated with clinicopathological features nor with recurrence. RNAseq identified a total of 387 differentially expressed genes, generating two clusters, being one enriched for short telomeres and CTNNB1-mutated aCPs.
Conclusions: CTNNB1
mutations are more frequent in children and adolescents and appear to associate with progressive disease. CTNNB1-mutated aCPs have shorter telomeres, demonstrating a relationship between the Wnt/β-catenin pathway and telomere biology in the pathogenesis of aCPs.
Supplementary Materials
- Supplementary Table 1. Down-regulated genes between adamantinomatous craniopharyngiomas (aCPs) RNA-seq clusters enriched by tumors with short telomere length and long telomere length.
- Supplementary Table 2. Up-regulated genes between adamantinomatous craniopharyngiomas (aCPs) RNA-seq clusters enriched by tumors with short telomere length and long telomere length.
- Supplementary Table 3. Top10 positive and Top10 negative related pathways identified by Gene Set Enrichment Analysis (GSEA) in adamantinomatous craniopharyngiomas according to telomere length ratio.
- Supplementary Table 4. Top10 positive and Top10 negative related pathways identified by Over Representation Analysis (ORA) in adamantinomatous craniopharyngiomas according to telomere length ratio.
