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Alternative Lengthening of Telomeres (ALT) and Telomerase Reverse Transcriptase Promoter Methylation in Recurrent Adult and Primary Pediatric Pituitary Neuroendocrine Tumors

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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.

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Acknowledgements

This research was supported by BimboTu ONLUS and Il Fondo di Gio ONLUS.

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Authors and Affiliations

  1. Department of Basic Medical Sciences, Faculty of Medicine, Yarmouk University, Irbid, Jordan

    Hiba Alzoubi

  2. Department of Radiological, Oncological and Anatomo-Pathological Sciences, Sapienza University of Rome, Rome, Italy

    Simone Minasi, Francesca Gianno, Manila Antonelli, Felice Giangaspero & Francesca Romana Buttarelli

  3. Department of Biotechnological and Applied Clinical Sciences, University of L’Aquila, L’Aquila, Italy

    Marie-Lise Jaffrain-Rea

  4. IRCCS Neuromed, Pozzilli, Italy

    Francesca Gianno, Felice Giangaspero & Marie-Lise Jaffrain-Rea

  5. Department of Molecular Medicine, Sapienza University of Rome, Rome, Italy

    Francesca Belardinilli

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Conceptualization: Hiba Alzoubi, Marie-Lise Jaffrain-Rea, Francesca Romana Buttarelli; Methodology, formal analysis, and investigation: Simone Minasi, Francesca Gianno; Writing-original draft preparation: Hiba Alzoubi, Simone Minasi; Writing-review and editing: Francesca Romana Buttarelli, Marie-Lise Jaffrain-Rea; Resources and formal analysis: Francesca Belardinilli, Marie-Lise Jaffrain-Rea, Manila Antonelli; Funding acquisition: Felice Giangaspero, Francesca Romana Buttarelli, Manila Antonelli; Supervision: Francesca Romana Buttarelli, Felice Giangaspero.

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Alzoubi, H., Minasi, S., Gianno, F. et al. Alternative Lengthening of Telomeres (ALT) and Telomerase Reverse Transcriptase Promoter Methylation in Recurrent Adult and Primary Pediatric Pituitary Neuroendocrine Tumors. Endocr Pathol 33, 494–505 (2022). https://doi.org/10.1007/s12022-021-09702-0

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