Chromosomal instability in the prediction of pituitary neuroendocrine tumors prognosis

Abstract

The purpose of this study was to analyze the impact of copy number variations (CNV) on sporadic pituitary neuroendocrine tumors (PitNETs) prognosis, to identify specific prognosis markers according to the known clinico-pathological classification. CGH array analysis was performed on 195 fresh-frozen PitNETs (56 gonadotroph, 11 immunonegative, 56 somatotroph, 39 lactotroph and 33 corticotroph), with 5 years post-surgery follow-up (124 recurrences), classified according to the five-tiered grading classification (invasion, Ki-67, mitotic index and p53 positivity). Effect of alterations on recurrence was studied using logistic regression models. Transcriptomic analysis of 32 lactotroph tumors was performed. The quantity of CNV was dependent on tumor type: higher in lactotroph (median(min–max) = 38% (0–97) of probes) compared to corticotroph (11% (0–77)), somatotroph (5% (0–99)), gonadotroph (0% (0–10)) and immunonegative tumors (0% (0–17). It was not predictive of recurrence in the whole cohort. In lactotroph tumors, genome instability, especially quantity of gains, significantly predicted recurrence independently of invasion and proliferation (p-value = 0.02, OR = 1.2). However, no specific CNV was found as a prognostic marker. Transcriptomic analysis of the genes included in the CNV and associated with prognosis didn’t show significantly overrepresented pathway. In somatotroph and corticotroph tumors, USP8 and GNAS mutations were not associated with genome disruption or recurrence respectively. To conclude, CGH array analysis showed genome instability was dependent on PitNET type. Lactotroph tumors were highly altered and the quantity of altered genome was associated with poorer prognosis though the mechanism is unclear, whereas gonadotroph and immunonegative tumors showed the same ‘quiet’ profile, leaving the mechanism underlying tumorigenesis open to question.

Aggressive corticotroph tumors and carcinomas

“…The quantity of chromosomal alterations was reported to be associated with invasion in a cohort of 27 pediatric Cushing's disease subjects, 45 and with macroadenomas, silent or Crooke's cell tumors, in another recent study on 22 patients 33 . In our study on 33 cortricotroph tumors, a higher level of CNVs seemed to be associated with macroadenomas, without reaching statistical significance, but was not associated with invasion, with silent tumors, nor with USP8 mutations 44 . Overall, we also failed to find an association between tumor recurrence at 5 years and the quantity of CNVs.…”

Phthalimide Analogs Enhance Genotoxicity of Cyclophosphamide and Inhibit Its Associated Hypoxia

“…The development of the carcinogenesis process is usually correlated with the abnormalities of chromosomes that mainly result from frequent mutations in genes that contribute in preserving the stability of the chromosomes ( Huang and Zhou, 2021 ). Those mutations evoke genomic instability events that can support tumor progression and further enhance metastasis ( Lasolle et al, 2020 ). Additionally, other rearrangements and/or deletions have been detected in tumor suppressor genes, and the substitution single base has been detected in cancer cell clones with multiple mutations that can activate oncogenes ( e.g ., MYC and RAS) and inhibit tumor suppressor genes such as TP53 ( Ma et al, 2021 ).…”

Pituitary tumors and the risk of other malignancies: is the relationship coincidental or causal?

“…The ability to accurately identify molecular signatures associated with histopathology and clinical outcomes is still not possible. Although a study of Lasolle et al did show that the quantity of copy number variations is dependent on tumor type (higher in prolactinomas) compared to other tumors, another study showed that all functional pituitary tumors demonstrated higher variability in copy-number profiles (Bi et al, 2017;Lasolle et al, 2020). As for aggressive and malignant pituitary tumors lactotroph tumors are the second most frequent after corticotrophinomas (McCormack et al, 2018).…”