Journal of Gastrointestinal Surgery

, Volume 12, Issue 1, pp 17–29

Telomere Shortening and Telomerase Expression during Multistage Carcinogenesis of Intraductal Papillary Mucinous Neoplasms of the Pancreas

  • Yasushi Hashimoto
  • Yoshiaki Murakami
  • Kenichiro Uemura
  • Yasuo Hayashidani
  • Takeshi Sudo
  • Hiroki Ohge
  • Emi Fukuda
  • Fumio Shimamoto
  • Taijiro Sueda
  • Eiso Hiyama
SSAT plenery paper

Abstract

Intraductal papillary mucinous neoplasm (IPMN) of the pancreas has been increasingly identified as a precursor to infiltrating ductal adenocarcinoma. Telomerase activation in response to telomere crisis followed by telomere shortening is thought to be a crucial event in the development of most human cancers. The aim of this study was to determine when this event occurs in the context of histologically defined IPMN progression. We analyzed telomerase expression in 68 IPMN samples and assessed telomere length by quantitative fluorescence in situ hybridization in samples taken from 17 sequential IPMN patients that included 37 individual loci. Samples from pancreatic ductal adenocarcinomas (PDACs, n = 15) and chronic pancreatitis patients (n = 10) were also examined. Telomeres were significantly shortened in 36 (97.3%) of 37 IPMN loci, with average telomere length decreasing with IPMN progression. Notably, even adenoma IPMNs demonstrated a 50% reduction of telomere length in 7 of 14 foci examined. Marked telomere shortening was observed from the in situ IPMN carcinoma stage (P < 0.001; vs borderline IPMNs) through the invasive stage, although telomerase had been activated, indicating that telomeres had shortened to a critical length by this histological grade. Up-regulated human telomerase reverse transcriptase expression was detectable and increased gradually with cancer development and was primarily observed at the borderline IPMN stage and then in more advanced histopathologies. Progressive telomere shortening predominantly occurs during early IPMNs carcinogenesis before telomerase activation and progression from borderline to carcinoma in situ IPMNs is the critical stage of IPMNs carcinogenesis at which telomere dysfunction occurs.

Keywords

Intraductal papillary mucinous neoplasm (IPMN) Telomere shortening Telomerase Human telomerase reverse transcriptase (hTERT) Pancreatic cancer Carcinogenesis 

Abbreviations

IPMN

intraductal papillary mucinous neoplasm

hTERT

human telomerase reverse transcriptase

IHC

immunohistochemistry

Q-FISH

quantitative fluorescence in situ hybridization

TRAP

telomeric repeat amplification protocol

PDAC

pancreatic ductal adenocarcinoma

TS

telomerase substrate

TPG

total product generated

TFI

telomere fluorescence intensity

ALT

alternative lengthening for telomeres

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Copyright information

© The Society for Surgery of the Alimentary Tract 2007

Authors and Affiliations

  • Yasushi Hashimoto
    • 1
  • Yoshiaki Murakami
    • 1
  • Kenichiro Uemura
    • 1
  • Yasuo Hayashidani
    • 1
  • Takeshi Sudo
    • 1
  • Hiroki Ohge
    • 1
  • Emi Fukuda
    • 1
  • Fumio Shimamoto
    • 4
  • Taijiro Sueda
    • 1
  • Eiso Hiyama
    • 2
    • 3
  1. 1.Department of Surgery, Division of Clinical Medical Science, Graduate School of Biomedical SciencesHiroshima UniversityHiroshimaJapan
  2. 2.Department of Biomedicine, Division of Clinical Medical Science, Graduate School of Biomedical SciencesHiroshima UniversityHiroshimaJapan
  3. 3.Natural Science Center of Basic Research and DevelopmentHiroshima UniversityHiroshimaJapan
  4. 4.Department of Pathology, Faculty of Human Culture and SciencePrefectural University of HiroshimaHiroshimaJapan

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