Abstract
Purpose of ReviewAlternative lengthening of telomeres (ALT) is a telomerase-independent mechanism used by some types of malignancies, including pancreatic neuroendocrine tumors, to overcome the issue of telomere shortening, thus supporting tumor growth and cell proliferation. This review is focused on the most important achievements and opportunities deriving from ALT assessment in PanNET onco-pathology, highlighting the most promising fields in which such biomarker could be implemented in clinical practice.Recent FindingsIn pancreatic neuroendocrine tumors (PanNET), ALT is strongly correlated with the mutational status of two chromatin remodeling genes, DAXX and ATRX. Recent advances in tumor biology permitted to uncover important roles of ALT in the landscape of PanNET, potentially relevant for introducing this biomarker into clinical practice. Indeed, ALT emerged as a reliable indicator of worse prognosis for PanNET, helping in clinical stratification and identification of “high-risk” patients. Furthermore, it is a very specific marker supporting the pancreatic origin of neuroendocrine neoplasms and can be used for improving the diagnostic workflow of patients presenting with neuroendocrine metastasis from unknown primary. The activation of this process can be determined by specific FISH analysis.SummaryALT should be introduced in clinical practice for identifying “high-risk” PanNET patients and improving their clinical management, and as a marker of pancreatic origin among neuroendocrine tumors.
Highlights
Since somatic cells are unable to polymerize all DNA during physiological replication, each round of cell divisionThis article is part of the Topical Collection on Neuroendocrine NeoplasmsPhysiologically, telomere shortening is counterbalanced by the specific activity of the enzyme telomerase, which is a DNA polymerase that uses reverse transcription of a RNA template to produce de novo synthesis of telomeric DNA [5]
Some neoplasms do not overcome the issue of telomere shortening by using telomerase, but maintain telomere length with a different process, which is totally telomerase-independent and called alternative lengthening of telomeres (ALT) [6,7]
A last insight regarding the potential clinical value of ALT in pancreatic neuroendocrine tumors (PanNET) has been provided by Hackeng et al that focused their analysis on a cohort of 31 patients with insulinomas and found that ALT phenotype was strictly associated with the risk of developing liver metastasis [22]
Summary
Telomere shortening is counterbalanced by the specific activity of the enzyme telomerase, which is a DNA polymerase that uses reverse transcription of a RNA template to produce de novo synthesis of telomeric DNA [5]. Curr Oncol Rep (2021) 23: 106 chromosome [8] Due to these different mechanisms, ALT cells usually show long and heterogeneous telomeres with sub-nuclear formations, the ALT-associated promyelocytic leukemia bodies (APB), which comprise telomeric DNA and the telomere-specific binding proteins, known as terminal restriction fragments (TRF) [8]. Thanks to these features, ALT status can be determined by specific FISH analysis (Fig. 1). The activation of the ALT mechanism emerged as a common process associated to the metastatic behavior of primary medulloblastomas [13] These findings highlight both the biological importance of ALT in tumor progression and its broad prognostic significance. We will analyze and discuss more in depth the most important findings related to ALT in PanNET, shedding light on its potential applications in clinical practice
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