TERT promoter mutations in gliomas, genetic associations and clinico-pathological correlations.

BACKGROUND: The role of telomerase reverse transcriptase (TERT) in gliomagenesis has been recently further strengthened by the frequent occurrence of TERT promoter mutations (TERTp-mut) in gliomas and evidence that the TERT SNP genetic rs2736100 influences glioma risk. TERTp-mut creates a binding site for Ets/TCF transcription factors, whereas the common rs2853669 polymorphism disrupts another Ets/TCF site on TERT promoter. METHODS: We sequenced for TERTp-mut in 807 glioma DNAs and in 235 blood DNAs and analysed TERT expression by RT-PCR in 151 samples. TERTp-mut status and TERTp polymorphism rs2853669 were correlated with histology, genomic profile, TERT mRNA expression, clinical outcome and rs2736100 genotype. RESULTS: TERTp-mut identified in 60.8% of gliomas (491 out of 807) was globally associated with poorer outcome (Hazard ratio (HR)=1.50). We defined, based on TERTp-mut and IDH mutation status, four prognostic groups: (1) TERTp-mut and IDH-mut associated with 1p19q codeletion, overall survival (OS)>17 years; (2) TERTp-wt and IDH-mut, associated with TP53 mutation, OS=97.5 months; (3) TERTp-wt and IDH-wt, with no specific association, OS=31.6 months; (4) TERTp-mut and IDH-wt, associated with EGFR amplification, OS=15.4 months. TERTp-mut was associated with higher TERT mRNA expression, whereas the rs2853669 variant was associated with lower TERT mRNA expression. The mutation of CIC (a repressor of ETV1-5 belonging to the Ets/TCF family) was also associated with TERT mRNA upregulation. CONCLUSIONS: In addition to IDH mutation status, defining the TERTp-mut status of glial tumours should afford enhanced prognostic stratification of patients with glioma. We also show that TERTp-mut, rs2853669 variant and CIC mutation influence Tert expression. This effect could be mediated by Ets/TCF transcription factors.

[Auxological data and definitive height in short patients without hormonal deficiencies. A longitudinal study]. / Dati auxologici e statura definitiva in pazienti iposomici senza deficit ormonali. Studio longitudinale.

61 children (49 males and 12 females) with stature before puberty less than 3. centile were studied. They had been previously diagnosed with the various GH stimulation tests as "constitutional short" and they were measured after reaching final adult height. During longitudinal follow-up, the following auxological data were calculated: height for chronological and bone age sds (HCAsds, HBAsds), height age/bone age ratio (HA/BA), bone age sds (BA sds); all the latter were calculated both in prepuberty and in puberty (mean 1.24 years after the onset of puberty). Target height and predictable height according to Bayley and Pinneau were also calculated. Final height for males was 152-175 cm (mean 162.3) and for females 144-163 cm (mean 151.5). These values were lower than expected with both target height and Bayley and Pinneau prediction, especially if the values of Bayley and Pinneau had been calculated before puberty. In females there was a significant positive correlation with target and final height. In males final height was positively correlated with Target height, with prepuberal data of HCA sds and with pubertal data of HBA sds and HA/BA. A negative correlation was found with final height in males and BA sds during puberty. A delay in bone age, probability, represented a positive factor in increasing final height only if it was maintained during puberty. Bayley and Pinneau's method overestimated final height, in particular when it was used before puberty or with a severe bone delay. Subject with pubertal delay are 2.42 cm taller than normal pubertal children. This difference had been acquired before puberty.