Intratumoral diversity of telomere length in individual neuroblastoma tumors
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Annalisa Pezzolo1, Angela Pistorio2, Claudio Gambini3 , Riccardo Haupt2, Manuela Ferraro3, Giovanni Erminio2, Bruno De Bernardi4, Alberto Garaventa4 and Vito Pistoia1
1 Laboratorio di Oncologia Istituto Giannina Gaslini Genova, Italy
2 Epidemiologia e Biostatistica Istituto Giannina Gaslini Genova, Italy
3 Laboratorio di Anatomia Patologica Istituto Giannina Gaslini Genova, Italy
4 Dipartimento di Emato-Oncologia Pediatrica Istituto Giannina Gaslini Genova, Italy
Annalisa Pezzolo, email:
Keywords: Telomere length, ALT mechanism, telomerase, neuroblastoma
Received: April 17, 2014 Accepted: June 17, 2014 Published: June 18, 2014
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.
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