Abstract

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.

Highlights

  • Telomere maintenance mechanisms (TMMs) are one of the hallmarks through which cancer cells develop indefinite proliferation capacity

  • Clinical and histopathological parameters of 58 sporadic pancreatic neuroendocrine neoplasms (pNENs) patients included in this study are summarized and grouped according to wild-type and C250T and C228T TERT promoter mutations (TPMs) (Tables 1 and 2)

  • Patients, e.g., advanced age and metastasis (p = 0.24–0.28). These observed trends may indicate a relation between TPMs and pNEN tumor progression

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Summary

Introduction

Telomere maintenance mechanisms (TMMs) are one of the hallmarks through which cancer cells develop indefinite proliferation capacity. Telomerase is a ribonucleoprotein and reverse transcriptase, which adds units of the repeated telomere core sequence to the distal chromosomal ends [3]. TA becomes activated in cancer cells by mechanisms including chromosome rearrangements, epigenetics and TERT promoter mutations (TPMs) [4]. These TPMs are the most frequent non-coding mutations in cancer that can occur early during tumorigenesis [5]. Two such human cancer-associated hot spot TPMs are cytidine-to-thymidine changes at genomic loci Chr5:1,295,228 (C228T) and 1,295,250 (C250T), located upstream of TERT transcription and translation start [6,7]

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