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

2021 ◽  
Vol 23 (9) ◽  
Author(s):  
Claudio Luchini ◽  
Rita T. Lawlor ◽  
Samantha Bersani ◽  
Caterina Vicentini ◽  
Gaetano Paolino ◽  
...  
Keyword(s):  
Clinical Practice ◽  
High Risk ◽  
Neuroendocrine Tumors ◽  
Tumor Biology ◽  
Specific Marker ◽  
Fish Analysis ◽  
Pancreatic Neuroendocrine Tumors ◽  
Alternative Lengthening Of Telomeres ◽  
Alternative Lengthening ◽  
Pancreatic Origin

Abstract 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. Summary 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.

scholarly journals Alternative lengthening of telomeres and ATRX/DAXX loss can be reliably detected in FNAs of pancreatic neuroendocrine tumors

2017 ◽  
Vol 125 (7) ◽  
pp. 544-551 ◽  
Author(s):  
Christopher J. VandenBussche ◽  
Derek B. Allison ◽  
Mindy K. Graham ◽  
Vivek Charu ◽  
Anne Marie Lennon ◽  
...  
Keyword(s):  
Neuroendocrine Tumors ◽  
Pancreatic Neuroendocrine Tumors ◽  
Alternative Lengthening Of Telomeres ◽  
Alternative Lengthening

CT Radiogenomic Characterization of the Alternative Lengthening of Telomeres Phenotype in Pancreatic Neuroendocrine Tumors

2018 ◽  
Vol 211 (5) ◽  
pp. 1020-1025 ◽  
Author(s):  
Jonathan M. McGovern ◽  
Aatur D. Singhi ◽  
Amir A. Borhani ◽  
Alessandro Furlan ◽  
Kevin M. McGrath ◽  
...  
Keyword(s):  
Neuroendocrine Tumors ◽  
Pancreatic Neuroendocrine Tumors ◽  
Alternative Lengthening Of Telomeres ◽  
Alternative Lengthening

scholarly journals Analysis of potential response predictors to capecitabine/temozolomide in metastatic pancreatic neuroendocrine tumors

2016 ◽  
Vol 23 (9) ◽  
pp. 759-767 ◽  
Author(s):  
M Cives ◽  
M Ghayouri ◽  
B Morse ◽  
M Brelsford ◽  
M Black ◽  
...  
Keyword(s):  
Neuroendocrine Tumors ◽  
Proliferative Activity ◽  
Dna Methyltransferase ◽  
Predictive Biomarkers ◽  
Pancreatic Neuroendocrine Tumors ◽  
Mgmt Expression ◽  
Methylguanine Dna Methyltransferase ◽  
Response Predictors ◽  
Alternative Lengthening ◽  
Pathway Activation

The capecitabine and temozolomide (CAPTEM) regimen is active in the treatment of metastatic pancreatic neuroendocrine tumors (pNETs), with response rates ranging from 30 to 70%. Small retrospective studies suggest that O6-methylguanine DNA methyltransferase (MGMT) deficiency predicts response to temozolomide. High tumor proliferative activity is also commonly perceived as a significant predictor of response to cytotoxic chemotherapy. It is unclear whether chromosomal instability (CIN), which correlates with alternative lengthening of telomeres (ALT), is a predictive factor. In this study, we evaluated 143 patients with advanced pNET who underwent treatment with CAPTEM for radiographic and biochemical response. MGMT expression (n=52), grade (n=128) and ALT activation (n=46) were investigated as potential predictive biomarkers. Treatment with CAPTEM was associated with an overall response rate (ORR) of 54% by RECIST 1.1. Response to CAPTEM was not influenced by MGMT expression, proliferative activity or ALT pathway activation. Based on these results, no biomarker-driven selection criteria for use of the CAPTEM regimen can be recommended at this time.

scholarly journals Most Prevalent Pancreatic Neuroendocrine Tumors in Everyday Clinical Practice

2014 ◽  
Vol 25 ◽  
pp. ii22
Author(s):  
Souza Iure ◽  
Vasques Lívia ◽  
Silva Sâmara ◽  
de Oliveira Mariana ◽  
de Paiva Vanessa
Keyword(s):  
Clinical Practice ◽  
Neuroendocrine Tumors ◽  
Pancreatic Neuroendocrine Tumors ◽  
Everyday Clinical Practice

Widespread somatic loss of heterozygosity as a possible marker of disease aggressiveness in metastatic well differentiated pancreatic neuroendocrine tumors.

2018 ◽  
Vol 36 (4_suppl) ◽  
pp. 275-275
Author(s):  
Omobolaji Oyekunle Akala ◽  
Ronak Shah ◽  
Brian R. Untch ◽  
Virginia Kelly ◽  
Joanne F. Chou ◽  
...  
Keyword(s):  
Loss Of Heterozygosity ◽  
Neuroendocrine Tumors ◽  
Copy Number ◽  
Tumor Biology ◽  
Genetic Alterations ◽  
Routine Practice ◽  
Tumor Type ◽  
Pancreatic Neuroendocrine Tumors ◽  
Pathologic Features ◽  
Well Differentiated

275 Background: To assess the utility of molecular profiling to predict tumor biology, we performed next-generation sequencing (NGS) of metastatic well differentiated (WD) pancreatic neuroendocrine tumors (panNETs) in the routine practice setting. Our institutional NGS platform allows for evaluation of genetic alterations that contribute to tumorigenesis (sequence variants, copy number alterations, insertions/deletions, select rearrangements) as well as somatic loss of heterozygosity (LOH). Methods: NGS was performed using MSK-IMPACT, a matched tumor-normal sequencing platform that interrogates 468 cancer-related genes. LOH for all cases was determined by analysis of total, allele-specific, and integer DNA copy number genome-wide using the FACETS algorithm. Results: Since 2014, NGS has been performed in 96 tumor samples from 80 patients. The most commonly altered genes were MEN1 (56%), DAXX (40%), ATRX (25%), and TSC2 (25%). LOH was highly prevalent, identified in 51/96 samples (53%). A significant association (q-value < 0.05) was noted between LOH and the presence of altered MEN1, DAXX, PTEN, or TSC2. LOH was recurrently observed in chromosomes 1, 2, 3, 6, 8, 10, 11, 15, 16, 21, and 22. Since MEN1 alterations predict improved outcome, comparison was made between patients with LOH present/MEN1 wild type (WT) tumors (n = 16) and LOH absent/MEN1 altered tumors (n = 21); inferior overall survival (OS) was noted with LOH present/MEN1 WT status (p < 0.01). High grade pathology was observed in 6/16 (38%) LOH present/MEN1 WT tumors and in 1/21 (5%) LOH absent/MEN1 altered tumors (p < 0.0001). The mean Ki-67 index of LOH present/MEN1 WT tumors was 22% and that of LOH absent/MEN1 altered tumors was 9%. Conclusions: This is the first study to report widespread somatic LOH in metastatic WD panNETs. PanNETs appear to exhibit more LOH overall than virtually any tumor type studied. In this cohort, LOH was a prognostic marker of inferior OS and was associated with more aggressive pathologic features. LOH warrants further investigation as it may help better characterize these clinically heterogeneous tumors.

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