Department of Basic Medical Sciences, Faculty of Medicine, Yarmouk University, Irbid, Jordan.
Department of Radiological, Oncological and Anatomo-Pathological Sciences, Sapienza University of Rome, Rome, Italy.
Endocr Pathol. 2022 Dec;33(4):494-505. doi: 10.1007/s12022-021-09702-0. Epub 2022 Jan 6.
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.
肿瘤细胞通过端粒酶或端粒的替代延长（ALT）来维持端粒，从而获得无限增殖的能力。端粒维持在垂体神经内分泌肿瘤（PitNETs）中的作用尚未被彻底研究。我们分析了 24 例成人复发性 PitNETs（包括 14 例的发病和复发）和 12 例儿童原发性 PitNETs 的手术样本。使用端粒特异性荧光原位杂交、端粒酶逆转录酶启动子（TERTp）甲基化的甲基化特异性 PCR 和 ATRX 免疫组织化学评估 ALT 的存在。在成人复发性 PitNETs 中，我们确定了 3/24（12.5%）ALT 阳性病例。ALT 从发病时存在，并在随后的复发中维持，表明这种机制发生在肿瘤发生的早期，并在进展过程中保持稳定。只有一个 ALT 阳性病例中出现了 ATRX 缺失。值得注意的是，在 5 例侵袭性 PitNETs 中有 3 例观察到 ALT，其中包括 2 例侵袭性促皮质素瘤，最终导致患者死亡。ALT 阴性肿瘤（87.5%）根据其低（29.2%）、中（50%）和高（8.3%）端粒荧光强度进行分类，其分子、临床和病理特征无显著差异。在 24 例病例中发现 6/24（25%）存在 TERTp 甲基化，在发病和复发时甲基化状态完全一致，表明该机制在整个疾病进展过程中保持稳定。TERTp 甲基化不影响端粒长度。在儿童 PitNETs 队列中，也观察到 4/12 例（33.3%）存在 TERTp 甲基化，但未观察到 ALT 激活。总之，ALT 在一部分成人 PitNETs 中在发病时被触发并在肿瘤进展过程中维持，这表明它可用于临床目的，作为侵袭性行为的潜在预测因子。
