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Article

Hot Spot TERT Promoter Mutations Are Rare in Sporadic Pancreatic Neuroendocrine Neoplasms and Associated with Telomere Length and Epigenetic Expression Patterns

1
Department of Medicine I, Division: Institute of Cancer Research, Comprehensive Cancer Center, Medical University of Vienna, 1090 Vienna, Austria
2
Institute of Pathology, Paracelsus Medical University/Salzburger Landeskliniken (SALK), 5020 Salzburg, Austria
3
Department of Visceral, Transplant and Thoracic Surgery, Medical University of Innsbruck, 6020 Innsbruck, Austria
4
Regional Medical Directorate of the Province of Salzburg, Office of the Salzburg Provincial Government, Sebastian-Stief-Gasse 2, 5020 Salzburg, Austria
5
Department of Surgery, Paracelsus Medical University, Salzburger Landeskliniken (SALK), 5020 Salzburg, Austria
6
Department of Internal Medicine I & Institute of Physiology and Pathophysiology, Paracelsus Medical University/Salzburger Landeskliniken (SALK), 5020 Salzburg, Austria
7
Yale Department of Chronic Disease Epidemiology, School of Public Health, School of Medicine, Yale Cancer Center, Yale University, New Haven, CT 06520-8034, USA
8
Department of Surgery, Salzkammergutkliniken, 4840 Vöcklabruck, Austria
*
Author to whom correspondence should be addressed.
These authors contributed equally to this work.
Cancers 2020, 12(6), 1625; https://doi.org/10.3390/cancers12061625
Received: 30 May 2020 / Revised: 15 June 2020 / Accepted: 18 June 2020 / Published: 19 June 2020
(This article belongs to the Special Issue The Role of Telomeres and Telomerase in Cancer)
Cancer cells activate a telomere maintenance mechanism like telomerase in order to proliferate indefinitely. Telomerase can be reactivated by gain-of-function Telomerase Reverse Transcriptase (TERT) promoter mutations (TPMs) that occur in several cancer subtypes with high incidence and association with diagnosis, prognosis and epigenetics. However, such information about TPMs in sporadic pancreatic neuroendocrine neoplasms (pNENs) including tumor (pNET) and carcinoma (pNEC) is less well defined. We have studied two hot spot TPMs and telomere length (TL) in pNEN and compared the results with clinicopathological information and proliferation-associated miRNA/HDAC expression profiles. DNA was isolated from formalin-fixed paraffin-embedded (FFPE) tissue of 58 sporadic pNEN patients. T allele frequency of C250T and C228T TPM was analyzed by pyrosequencing, relative TL as telomeric content by qPCR. In total, five pNEN cases (9%) including four pNETs and one pNEC were identified with TPMs, four cases with exclusive C250T as predominant TPM and one case with both C250T and C228T. T allele frequencies of DNA isolated from adjacent high tumor cell content FFPE tissue varied considerably, which may indicate TPM tumor heterogeneity. Overall and disease-free survival was not associated with TPM versus wild-type pNEN cases. Binary category analyses indicated a marginally significant relationship between TPM status and longer telomeres (p = 0.086), and changes in expression of miR449a (p = 0.157), HDAC4 (p = 0.146) and HDAC9 (p = 0.149). Future studies with larger patient cohorts are needed to assess the true clinical value of these rare mutations in pNEN. View Full-Text
Keywords: pancreatic neuroendocrine tumor; TERT promoter mutation; telomere length; tumor heterogeneity; pyrosequencing; microRNA; histone deacetylase pancreatic neuroendocrine tumor; TERT promoter mutation; telomere length; tumor heterogeneity; pyrosequencing; microRNA; histone deacetylase
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MDPI and ACS Style

Posch, A.; Hofer-Zeni, S.; Klieser, E.; Primavesi, F.; Naderlinger, E.; Brandstetter, A.; Filipits, M.; Urbas, R.; Swiercynski, S.; Jäger, T.; Winkelmann, P.; Kiesslich, T.; Lu, L.; Neureiter, D.; Stättner, S.; Holzmann, K. Hot Spot TERT Promoter Mutations Are Rare in Sporadic Pancreatic Neuroendocrine Neoplasms and Associated with Telomere Length and Epigenetic Expression Patterns. Cancers 2020, 12, 1625. https://doi.org/10.3390/cancers12061625

AMA Style

Posch A, Hofer-Zeni S, Klieser E, Primavesi F, Naderlinger E, Brandstetter A, Filipits M, Urbas R, Swiercynski S, Jäger T, Winkelmann P, Kiesslich T, Lu L, Neureiter D, Stättner S, Holzmann K. Hot Spot TERT Promoter Mutations Are Rare in Sporadic Pancreatic Neuroendocrine Neoplasms and Associated with Telomere Length and Epigenetic Expression Patterns. Cancers. 2020; 12(6):1625. https://doi.org/10.3390/cancers12061625

Chicago/Turabian Style

Posch, Alexandra, Sarah Hofer-Zeni, Eckhard Klieser, Florian Primavesi, Elisabeth Naderlinger, Anita Brandstetter, Martin Filipits, Romana Urbas, Stefan Swiercynski, Tarkan Jäger, Paul Winkelmann, Tobias Kiesslich, Lingeng Lu, Daniel Neureiter, Stefan Stättner, and Klaus Holzmann. 2020. "Hot Spot TERT Promoter Mutations Are Rare in Sporadic Pancreatic Neuroendocrine Neoplasms and Associated with Telomere Length and Epigenetic Expression Patterns" Cancers 12, no. 6: 1625. https://doi.org/10.3390/cancers12061625

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