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 adenomas (PAs) has yet to be thoroughly investigated.
We propose to examine 40 adult recurrent PAs (analyzing both onset and relapses) and 20 pediatric primary PAs. The presence of ALT will be assessed using telomere-specific fluorescence in situ hybridization, telomerase reverse transcriptase promoter (TERTp) methylation by methylation-specific PCR, and ATRX expression by immunohistochemistry.
In conclusion, we will elucidate wether ALT could be triggered at onset and maintained in progression of adult PAs, as well as pediatric cases as comparison, in the wiew of a possible use for diagnostic purposes, as a predictor of a higher probability of recurrences, starting soon after the onset of these tumors.
Pituitary adenomas form a heterogeneous group of neoplasms with the immunophenotypic and hormonal characteristics of endocrine cells of the adenohypophysis. The WHO Classification of Tumors of Endocrine Organs classifies PAs as corticotroph, somatotroph, lactotroph, thyrotroph, gonadotroph or null-cell, depending on their hormone production and expression of transcription factors PIT1, SF1, and T-PIT [2,5]. Recent genomic studies showed that sporadic pituitary adenomas have low mutational burdens: only a few recurrent alterations were found, such as GNAS-activating mutations, mutations in the deubiquitinase gene USP8, and copy-number variations [6,7,9,10,11,13].
To date, only one study has reported on the presence of ALT in PAs [41]. The Authors found ALT in 3 (2.8%) of 106 PAs, and 2 of them were recurrent tumors. These results led them to analyze a second cohort of 32 patients with recurrent PAs, and they found that 8 (36%) of them were ALT-positive. The Authors concluded that ALT was enhanced in recurrent PA [41].
In the present study we will analyze 40 adult recurrent PAs, including patients with second recurrence and metastasis. We will examine cases of ALT activation and mean telomere fluorescence intensity, as well as ATRX loss and TERTp methylation. We will correlate our findings with patients¿ molecular and clinicopathological features. We will also investigate both the primary tumors and the relapses to clarify how this tumor progresses and seek any association with telomere length. We will analize a second cohort of 20 pediatric patients with primary PA as well because no previous studies had analyzed ALT activation or TERTp methylation in pediatric PAs, and because telomerase-targeted and ALT-targeted therapies might hold promise for pediatric tumors in general.
In conclusion, this study will investigate wether adult recurrent PAs may feature ALT activation, correlation with sex, with a specific hormon-secreting tumors, and correlation with recurrences; finally could elucidate the relationship to the tumor¿s metastatic potential. our study will clarify if telomere maintenance mechanism is activated in the tumor¿s development, and maintained as the disease progresses.
our study will add informations wether ALT may be useful in the diagnostic workup of adults and/or pediatric PA as a potential predictor of aggressive behavior. Multiple ALT-targeted drugs have recently been tested on several types of cancer, including recombination inhibitors, histone deacetylase (HDAC) inhibitors, or G-quadruplex stabilizer [51-53]; all these therapies might be promising as a strategy for treating aggressive recurrent adenomas, further studies are needed to validate and extend the knowledge on ALT-activated tumors.
Further references:
50)-Miyake Y, et al. doi:10.1007/s11060-018-03016-8.
52)-Kent T, et al. doi: 10.3389/fonc.2019.01518.
53)-Minasi S, et al. doi:10.4103/glioma.glioma_20_20.
54)-Sommer A, Royle NJ. doi: 10.3390/genes11020133.