Telomere length and Wnt/ß-catenin pathway in adamantinomatous craniopharyngiomas.

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/ß-catenin pathway and telomere biology in the pathogenesis of aCPs.

Urinary calcium excretion and insulin resistance in patients with acromegaly.

BACKGROUND: Renal complications in acromegaly include glomerular hyperfiltration, insulin resistance, hypercalciuria and urolithiasis. The aim of this study was to investigate whether urinary calcium (U(Ca)) excretion is a direct consequence of growth hormone secretion or secondary to hyperfiltration and/or insulin resistance. METHODS: We performed a cross-sectional study of 58 patients diagnosed with acromegaly. Demographic data were obtained, serum analysis was performed, including insulin-like growth factor (IGF)-1, and 24-h urine collection, to measure urinary protein excretion, U(Ca) and phosphate excretion, as well as fractional excretion of sodium and potassium. We also calculated the homeostasis model assessment of insulin resistance (HOMA-IR). RESULTS: Patients were predominantly male (60.3%), and their mean age was 45.9 ± 14 years. Hypercalciuria was present in 24% of patients. Patients with higher HOMA-IR had higher IGF-1 levels, a trend toward higher body mass index and higher U(Ca) excretion. In univariate analysis, U(Ca) excretion was associated with HOMA-IR (r = 0.472, P = 0.001), phosphaturia (r = 0.457, P = 0.001), IGF-1 (r = 0.398, P = 0.002) and creatinine clearance (r = 0.394, P = 0.001). HOMA-IR and phosphaturia were independently associated with U(Ca) excretion. No independent associations were found between phosphaturia and HOMA-IR or IGF-1. CONCLUSIONS: The present study revealed an association between hypercalciuria and insulin resistance in patients with acromegaly. Further studies are required to fully understand the pathogenesis of these abnormalities in patients with acromegaly.