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Telomere Shortening and Telomerase Expression During Multistage Carcinogenesis of Intraductal Papillary-Mucinous Neoplasm of the Pancreas
Yasushi Hashimoto*1, Yoshiaki Murakami1, Kenichiro Uemura1, Yasuo Hayashidani1, Takeshi Sudo1, Hiroki Ohge1, Emi Fukuda1, Fumio Shimamoto3, Taijiro Sueda1, Eiso Hiyama2
1Department of Surgery, Graduate School of Biomedical Sciences, Hiroshima University, Hiroshima, Japan; 2Department of Biomedicine, Graduate School of Biomedical Sciences and Natural Science Center of Basic Research and Development, Hiroshima University, Hiroshima, Japan; 3Department of Pathology, Faulty of Human Culture and Science, Prefectural University of Hiroshima, Hiroshima, Japan

Backgrounds: Telomere shortening is thought to be one of the mechanisms leading to chromosomal instability and cancer initiation. Maintenance of telomeres through activation of telomerase is an indispensable requisite for tumors to preserve their ability to proliferate. Although evidence for telomeric dysfunction has been demonstrated in pancreatic ductal adenocarcinoma (PDAC), the mechanisms of telomerase activation during carcinogenesis of intraductal papillary-mucinous neoplasms (IPMNs) of the pancreas remain unclear.Objectives: To evaluate telomerase expression and where transition through telomere crisis occurs during multistage carcinogenesis of IPMNs as a risk factor of susceptibility to development of cancer.Materials and
Methods: hTERT expression was examined by immunohistochemistry in 40 patients who underwent pancreatic resection for IPMNs. Telomere length was assessed using quantitative fluorescence in situ hybridization in representative samples derived from these patients. Samples from PDAC (n=10) and chronic pancreatitis (n=10) were also examined. Semi-quantitative telomerase activity was performed using the TRAP assay.
Results:The levels of telomerase activity were 1.01±1.22, 3.52±1.42, 11.21±10.08, 39.27±19.49 in adenoma, borderline, non-invasive, and invasive IPMN, respectively. hTERT was detectable in 2 of 10 adenoma, 4 of 10 borderline, 7 of 10 non-invasive, and 8 of 10 invasive IPMNs, which was observed primarily at the stage of precancerous lesions as well as adenoma, and borderline lesions. Telomere shortening were nearly universal (95.0% of cases) in the preinvasive stages of IPMN compared to adjacent normal structures, showing a gradual decrease of average telomere length. Even in adenoma IPMNs, the earliest putative precursor lesion, the samples demonstrated a reduction of telomere length (P=0.003). Notably, above the level of non-invasive IPMN, no further shortening of telomeres was found at the same level as PDAC (P=0.275), indicating that telomeres had reached a critically short length at this stage of histological grade. Histologically “uniform” pancreatic epithelial cells exhibited heterogenous telomere length in the preinvasive stage of IPMNs with no visible alteration in cellular appearance, and such epithelia may precede transformation and predispose the lesion to cancer development followed by activation of telomerase.
Conclusions: Telomere shortening represents an early and prevalent genetic abnormality acquired in the multistage carcinogenesis of IPMN, which predominate in non-invasive or more advanced lesions of IPMNs, with telomerase activation being prominent during the latter stages.

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