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

Cancers

Tobias Kiesslich¹  Elisabeth Naderlinger²  Alexandra Posch²  Anita Brandstetter²  Martin Filipits²  Klaus Holzmann²  Sarah Hofer-Zeni²  Stefan Swiercynski³  Tarkan Jäger³  Florian Primavesi⁴  Stefan Stättner⁴  Paul Winkelmann⁵  Eckhard Klieser⁵  Daniel Neureiter⁵  Romana Urbas⁶  Lingeng Lu⁷ 

[1] Department of Internal Medicine I & Institute of Physiology and Pathophysiology, Paracelsus Medical University/Salzburger Landeskliniken (SALK), 5020 Salzburg, Austria;Department of Medicine I, Division: Institute of Cancer Research, Comprehensive Cancer Center, Medical University of Vienna, 1090 Vienna, Austria;Department of Surgery, Paracelsus Medical University, Salzburger Landeskliniken (SALK), 5020 Salzburg, Austria;Department of Visceral, Transplant and Thoracic Surgery, Medical University of Innsbruck, 6020 Innsbruck, Austria;Institute of Pathology, Paracelsus Medical University/Salzburger Landeskliniken (SALK), 5020 Salzburg, Austria;Regional Medical Directorate of the Province of Salzburg, Office of the Salzburg Provincial Government, Sebastian-Stief-Gasse 2, 5020 Salzburg, Austria;Yale Department of Chronic Disease Epidemiology, School of Public Health, School of Medicine, Yale Cancer Center, Yale University, New Haven, CT 06520-8034, USA;

关键词: pancreatic neuroendocrine tumor;    TERT promoter mutation;    telomere length;    tumor heterogeneity;    pyrosequencing;    microRNA;   

DOI  :  10.3390/cancers12061625

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown