Gradual telomere shortening and increasing chromosomal instability among PanIN grades and normal ductal epithelia with and without cancer in the pancreas

PLoS One. 2015 Feb 6;10(2):e0117575. doi: 10.1371/journal.pone.0117575. eCollection 2015.

Abstract

A large body of evidence supports a key role for telomere dysfunction in carcinogenesis due to the induction of chromosomal instability. To study telomere shortening in precancerous pancreatic lesions, we measured telomere lengths using quantitative fluorescence in situ hybridization in the normal pancreatic duct epithelium, pancreatic intraepithelial neoplasias (PanINs), and cancers. The materials employed included surgically resected pancreatic specimens without cancer (n = 33) and with invasive ductal carcinoma (n = 36), as well as control autopsy cases (n = 150). In comparison with normal ducts, telomere length was decreased in PanIN-1, -2 and -3 and cancer. Furthermore, telomeres were shorter in cancer than in PanIN-1 and -2. Telomere length in cancer was not associated with histological type, lesion location, or cancer stage. PanINs with or without cancer showed similar telomere lengths. The incidences of atypical mitosis and anaphase bridges, which are morphological characteristics of chromosomal instability, were negatively correlated with telomere length. The telomeres in normal duct epithelium became shorter with aging, and those in PanINs or cancers were shorter than in age-matched controls, suggesting that telomere shortening occurs even when histological changes are absent. Our data strongly suggest that telomere shortening occurs in the early stages of pancreatic carcinogenesis and progresses with precancerous development. Telomere shortening and chromosomal instability in the duct epithelium might be associated with carcinogenesis of the pancreas. Determination of telomere length in pancreatic ductal lesions may be valuable for accurate detection and risk assessment of pancreatic cancer.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Carcinoma in Situ / genetics
  • Carcinoma in Situ / metabolism
  • Carcinoma in Situ / pathology*
  • Chromosomal Instability / genetics*
  • Epithelium / metabolism
  • Epithelium / pathology*
  • Humans
  • Pancreas / metabolism
  • Pancreas / pathology*
  • Pancreatic Neoplasms / genetics
  • Pancreatic Neoplasms / metabolism
  • Pancreatic Neoplasms / pathology*
  • Telomere / genetics
  • Telomere / pathology*
  • Telomere Shortening*

Grant support

This work was supported in part by a grant-in-aid from the Japan Society for the Promotion of Science (C, No. 25462127) and grants from the Cancer Research Institute of Kanazawa University and the Alumni Association of Kagawa University Faculty of Medicine Sanjukai to Y. Matsuda. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.