Neoplastic cells acquire the ability to proliferate endlessly by maintaining telomeres via telomerase, or alternative lengthening of telomeres (ALT). The role of telomere maintenance in pituitary neuroendocrine tumors (PitNETs) has yet to be thoroughly investigated. We analyzed surgical samples of 24 adult recurrent PitNETs (including onset and relapses for 14 of them) and 12 pediatric primary PitNETs. The presence of ALT was assessed using telomere-specific fluorescence in situ hybridization, methylation of telomerase reverse transcriptase promoter (TERTp) by methylation-specific PCR, and ATRX expression by immunohistochemistry. Among the adult recurrent PitNETs, we identified 3/24 (12.5%) ALT-positive cases. ALT was present from the onset and maintained in subsequent relapses, suggesting that this mechanism occurs early in tumorigenesis and is stable during progression. ATRX loss was only seen in one ALT-positive case. Noteworthy, ALT was observed in 3 out of 5 aggressive PitNETs, including two aggressive corticotroph tumors, eventually leading to patient’s death. ALT-negative tumors (87.5%) were classified according to their low (29.2%), medium (50%), and high (8.3%) telomere fluorescence intensity, with no significant differences emerging in their molecular, clinical, or pathological characteristics. TERTp methylation was found in 6/24 cases (25%), with a total concordance in methylation status between onset and recurrences, suggesting that this mechanism remains stable throughout disease progression. TERTp methylation did not influence telomere length. In the pediatric cohort of PitNETs, TERTp methylation was also observed in 4/12 cases (33.3%), but no case of ALT activation was observed. In conclusion, ALT is triggered at onset and maintained during tumor progression in a subset of adult PitNETs, suggesting that it could be used for clinical purposes, as a potential predictor of aggressive behavior.

Alternative lengthening of telomeres (ALT) and telomerase reverse transcriptase promoter methylation in recurrent adult and primary pediatric pituitary neuroendocrine tumors / Alzoubi, Hiba; Minasi, Simone; Gianno, Francesca; Antonelli, Manila; Belardinilli, Francesca; Giangaspero, Felice; Jaffrain-Rea, Marie-Lise; Buttarelli, Francesca Romana. - In: ENDOCRINE PATHOLOGY. - ISSN 1559-0097. - (2022). [10.1007/s12022-021-09702-0]

Alternative lengthening of telomeres (ALT) and telomerase reverse transcriptase promoter methylation in recurrent adult and primary pediatric pituitary neuroendocrine tumors

Simone Minasi
Secondo
;
Francesca Gianno;Manila Antonelli;Francesca Belardinilli;Felice Giangaspero;Francesca Romana Buttarelli
Ultimo
2022

Abstract

Neoplastic cells acquire the ability to proliferate endlessly by maintaining telomeres via telomerase, or alternative lengthening of telomeres (ALT). The role of telomere maintenance in pituitary neuroendocrine tumors (PitNETs) has yet to be thoroughly investigated. We analyzed surgical samples of 24 adult recurrent PitNETs (including onset and relapses for 14 of them) and 12 pediatric primary PitNETs. The presence of ALT was assessed using telomere-specific fluorescence in situ hybridization, methylation of telomerase reverse transcriptase promoter (TERTp) by methylation-specific PCR, and ATRX expression by immunohistochemistry. Among the adult recurrent PitNETs, we identified 3/24 (12.5%) ALT-positive cases. ALT was present from the onset and maintained in subsequent relapses, suggesting that this mechanism occurs early in tumorigenesis and is stable during progression. ATRX loss was only seen in one ALT-positive case. Noteworthy, ALT was observed in 3 out of 5 aggressive PitNETs, including two aggressive corticotroph tumors, eventually leading to patient’s death. ALT-negative tumors (87.5%) were classified according to their low (29.2%), medium (50%), and high (8.3%) telomere fluorescence intensity, with no significant differences emerging in their molecular, clinical, or pathological characteristics. TERTp methylation was found in 6/24 cases (25%), with a total concordance in methylation status between onset and recurrences, suggesting that this mechanism remains stable throughout disease progression. TERTp methylation did not influence telomere length. In the pediatric cohort of PitNETs, TERTp methylation was also observed in 4/12 cases (33.3%), but no case of ALT activation was observed. In conclusion, ALT is triggered at onset and maintained during tumor progression in a subset of adult PitNETs, suggesting that it could be used for clinical purposes, as a potential predictor of aggressive behavior.
2022
telomere; ALT; ATRX; TERTp methylation; pituitary neuroendocrine tumors
01 Pubblicazione su rivista::01a Articolo in rivista
Alternative lengthening of telomeres (ALT) and telomerase reverse transcriptase promoter methylation in recurrent adult and primary pediatric pituitary neuroendocrine tumors / Alzoubi, Hiba; Minasi, Simone; Gianno, Francesca; Antonelli, Manila; Belardinilli, Francesca; Giangaspero, Felice; Jaffrain-Rea, Marie-Lise; Buttarelli, Francesca Romana. - In: ENDOCRINE PATHOLOGY. - ISSN 1559-0097. - (2022). [10.1007/s12022-021-09702-0]
File allegati a questo prodotto
File Dimensione Formato  
Alzoubi_Alternative Lengthening of_2022.pdf

solo gestori archivio

Tipologia: Versione editoriale (versione pubblicata con il layout dell'editore)
Licenza: Tutti i diritti riservati (All rights reserved)
Dimensione 2.12 MB
Formato Adobe PDF
2.12 MB Adobe PDF   Contatta l'autore

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11573/1601150
Citazioni
  • ???jsp.display-item.citation.pmc??? 2
  • Scopus 3
  • ???jsp.display-item.citation.isi??? 3
social impact