Alternative Lengthening of Telomeres (ALT) in Pancreatic Neuroendocrine Tumors: Ready for Prime-Time in Clinical Practice?

Published on Jul 16, 2021in Current Oncology Reports3.828
· DOI :10.1007/S11912-021-01096-W
Claudio Luchini31
Estimated H-index: 31
Rita T. Lawlor31
Estimated H-index: 31
+ 7 AuthorsAldo Scarpa99
Estimated H-index: 99
PURPOSE OF REVIEW Alternative 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 FINDINGS In 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. ALT 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.
#1Wenzel M. Hackeng (UU: Utrecht University)H-Index: 7
#2Willemien Schelhaas (UvA: University of Amsterdam)H-Index: 1
Last. Lodewijk A.A. Brosens (UU: Utrecht University)H-Index: 25
view all 12 authors...
Insulin-producing pancreatic neuroendocrine tumors (PanNETs)/insulinomas are generally considered to be indolent tumors with an excellent prognosis after complete resection. However, some insulinomas have a poor prognosis due to relapses and metastatic disease. Recently, studies in non-functional PanNETs indicated that behavior can be stratified according to alpha- and beta-cell differentiation, as defined by expression of the transcription factors ARX and PDX1, respectively. It is unknown wheth...
12 CitationsSource
#1Antonio Pea (JHUSOM: Johns Hopkins University School of Medicine)H-Index: 19
#2Jun Yu (JHUSOM: Johns Hopkins University School of Medicine)H-Index: 154
Last. Ammar A. Javed (JHUSOM: Johns Hopkins University School of Medicine)H-Index: 23
view all 25 authors...
Objective: :The aim of this study was to investigate the key molecular alterations in small primary pancreatic neuroendocrine tumors (PanNETs) associated with the development of liver metastases.Background:Well-differentiated PanNETs with small size are typically indolent; however, a limited subset
38 CitationsSource
#1Mónica S. Ventura Ferreira (RWTH Aachen University)H-Index: 14
#2Mia Dahl Sørensen (University of Southern Denmark)H-Index: 4
Last. Fabian Beier (RWTH Aachen University)H-Index: 17
view all 9 authors...
Isocitrate dehydrogenase 1 (IDH1) mutations are associated with improved survival in gliomas. Depending on the IDH1 status, TERT promoter mutations affect prognosis. IDH1 mutations are associated with alpha-thalassemia/mental retardation syndrome X-linked (ATRX) mutations and alternative lengthening of telomeres (ALT), suggesting an interaction between IDH1 and telomeres. However, little is known how IDH1 mutations affect telomere maintenance. We analyzed cell-specific telomere length (CS-TL) on...
9 CitationsSource
#1Eric T. Sugarman (UPenn: University of Pennsylvania)H-Index: 2
#2Gao Zhang (Duke University)H-Index: 30
Last. Jerry W. Shay (UTSW: University of Texas Southwestern Medical Center)H-Index: 151
view all 3 authors...
: Engaging a telomere maintenance mechanism during DNA replication is essential for almost all advanced cancers. The conversion from normal and premalignant somatic cells to advanced malignant cells often results (85%-90%) from the reactivation of the functional ribonucleoprotein holoenzyme complex, referred to as telomerase. Modulation of the human telomerase reverse transcriptase (hTERT) appears to be rate limiting to produce functional telomerase and engage a telomere maintenance mechanism. T...
20 CitationsSource
: Gastroenteropancreatic (GEP) neuroendocrine neoplasms (NENs) are heterogeneous regarding site of origin, biological behavior, and malignant potential. There has been a rapid increase in data publication during the last 10 years, mainly driven by high-throughput studies on pancreatic and small intestinal neuroendocrine tumors (NETs). This review summarizes the present knowledge on genetic and epigenetic alterations. We integrated the available information from each compartment to give a pathway...
60 CitationsSource
#1Rita T. LawlorH-Index: 31
#2Nicola Veronese (National Research Council)H-Index: 69
Last. Claudio LuchiniH-Index: 31
view all 10 authors...
Background Alternative lengthening of telomeres (ALT) is a telomerase-independent mechanism used by a broad range of neoplasms to maintain telomere length, permitting uncontrolled replication during their progression. ALT has been described in different types of sarcoma, but a comprehensive analysis of its clinical significance is still lacking. Therefore, we provide here the first meta-analysis on this topic.
21 CitationsSource
#1Simone Minasi (Sapienza University of Rome)H-Index: 3
#2Caterina Baldi (Sapienza University of Rome)H-Index: 6
Last. Francesca R. Buttarelli (Sapienza University of Rome)H-Index: 24
view all 9 authors...
Purpose Elongation of telomeres is necessary for tumor cell immortalization and senescence escape; neoplastic cells use to alternative pathways to elongate telomeres: telomerase reactivation or a telomerase-independent mechanism termed alternative lengthening of telomeres (ALT). Telomerase and ALT pathway has been explored in adult and pediatric gliomas and medulloblastomas (MDBs); however, these mechanisms were not previously investigated in MDBs metastatic at the onset. Therefore, we analyzed ...
8 CitationsSource
#1Tiago Bordeira Gaspar (University of Porto)H-Index: 2
#2Ana Sá (University of Porto)H-Index: 1
Last. João Vinagre (University of Porto)H-Index: 17
view all 6 authors...
Tumour cells can adopt telomere maintenance mechanisms (TMMs) to avoid telomere shortening, an inevitable process due to successive cell divisions. In most tumour cells, telomere length (TL) is maintained by reactivation of telomerase, while a small part acquires immortality through the telomerase-independent alternative lengthening of telomeres (ALT) mechanism. In the last years, a great amount of data was generated, and different TMMs were reported and explained in detail, benefiting from geno...
55 CitationsSource
#1Christopher J. VandenBussche (JHUSOM: Johns Hopkins University School of Medicine)H-Index: 22
#2Derek B. Allison (JHUSOM: Johns Hopkins University School of Medicine)H-Index: 10
Last. Christopher M. Heaphy (Johns Hopkins University)H-Index: 27
view all 8 authors...
BACKGROUND Pancreatic neuroendocrine tumors (PanNETs) frequently use the alternative lengthening of telomeres (ALT) pathway for telomere maintenance. ALT is strongly correlated with α thalassemia-mental retardation, X linked (ATRX), and death domain-associated protein 6 (DAXX) alterations and a poor prognosis in patients with primary PanNET. Because fine-needle aspiration (FNA) is a noninvasive way to sample tumors, the authors evaluated whether they could accurately detect ALT and loss of ATRX/...
27 CitationsSource
#1Joo Young Kim (KU: Korea University)H-Index: 27
#2Jacqueline A. Brosnan-Cashman (Johns Hopkins University)H-Index: 9
Last. Seung-Mo Hong (UOU: University of Ulsan)H-Index: 59
view all 14 authors...
Purpose: Alternative lengthening of telomeres (ALT), a telomerase-independent telomere maintenance mechanism, is strongly associated with ATRX and DAXX alterations and occurs frequently in pancreatic neuroendocrine tumors (PanNET). Experimental Design: In a Korean cohort of 269 surgically resected primary PanNETs and 19 sporadic microadenomas, ALT status and nuclear ATRX and DAXX protein expression were assessed and compared with clinicopathologic factors. Results: In PanNETs, ALT or loss of ATR...
63 CitationsSource
Cited By0