title: Intratumoral diversity of telomere length in individual neuroblastoma tumors.
abstract: The purpose of the work was to investigate telomere length (TL) and mechanisms involved in TL maintenance in individual neuroblastoma (NB) tumors. Primary NB tumors from 102 patients, ninety Italian and twelve Spanish, diagnosed from 2000 to 2008 were studied. TL was investigated by quantitative fluorescence in situ hybridization (IQ-FISH) that allows to analyze individual cells in paraffin-embedded tissues. Fluorescence intensity of chromosome 2 centromere was used as internal control to normalize TL values to ploidy. Human telomerase reverse transcriptase (hTERT) expression was detected by immunofluorescence in 99/102 NB specimens.The main findings are the following: 1) two intratumoral subpopulations of cancer cells displaying telomeres of different length were identified in 32/102 tumors belonging to all stages. 2) hTERT expression was detected in 99/102 tumors, of which 31 displayed high expression and 68 low expression. Alternative lengthening of telomeres (ALT)-mechanism was present in 60/102 tumors, 20 of which showed high hTERT expression. Neither ALT-mechanism nor hTERT expression correlated with heterogeneous TL. 3) High hTERT expression and ALT positivity were associated with significantly reduced Overall Survival. 4) High hTERT expression predicted relapse irrespective of patient age. Intratumoral diversity in TL represents a novel feature in NB.In conclusion, diversity of TL in individual NB tumors was strongly associated with disease progression and death, suggesting that these findings are of translational relevance. The combination of high hTERT expression and ALT positivity may represent a novel biomarker of poor prognosis that deserves further investigation.
authors.affiliation: Laboratorio di Oncologia, Istituto Giannina Gaslini, Genova, Italy.
authors.forename: Annalisa
authors.initials: A
authors.lastname: Pezzolo
authors.affiliation: Epidemiologia e Biostatistica, Istituto Giannina Gaslini, Genova, Italy.
authors.forename: Angela
authors.initials: A
authors.lastname: Pistorio
authors.affiliation: Laboratorio di Anatomia Patologica, Istituto Giannina Gaslini, Genova, Italy.
authors.forename: Claudio
authors.initials: C
authors.lastname: Gambini
authors.affiliation: Epidemiologia e Biostatistica, Istituto Giannina Gaslini, Genova, Italy.
authors.forename: Riccardo
authors.initials: R
authors.lastname: Haupt
authors.affiliation: Laboratorio di Anatomia Patologica, Istituto Giannina Gaslini, Genova, Italy.
authors.forename: Manuela
authors.initials: M
authors.lastname: Ferraro
authors.affiliation: Epidemiologia e Biostatistica, Istituto Giannina Gaslini, Genova, Italy.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Erminio
authors.affiliation: Dipartimento di Emato-Oncologia Pediatrica, Istituto Giannina Gaslini, Genova, Italy.
authors.forename: Bruno
authors.initials: B
authors.lastname: De Bernardi
authors.affiliation: Dipartimento di Emato-Oncologia Pediatrica, Istituto Giannina Gaslini, Genova, Italy.
authors.forename: Alberto
authors.initials: A
authors.lastname: Garaventa
authors.affiliation: Laboratorio di Oncologia, Istituto Giannina Gaslini, Genova, Italy.
authors.forename: Vito
authors.initials: V
authors.lastname: Pistoia
mesh_terms: D045744:Cell Line, Tumor; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D008297:Male; D009447:Neuroblastoma / Q000235:genetics* / Q000401:mortality; D012189:Retrospective Studies; D016019:Survival Analysis; D019098:Telomerase / Q000235:genetics*; D016615:Telomere / Q000378:metabolism*
chemical_list: D019098:Telomerase
keywords: ALT mechanism; neuroblastoma; telomerase; telomere length