Increased DNA methyltransferase 1 (DNMT1) protein expression in precancerous conditions and ductal carcinomas of the pancreas - PubMed (original) (raw)

Increased DNA methyltransferase 1 (DNMT1) protein expression in precancerous conditions and ductal carcinomas of the pancreas

Dun-Fa Peng et al. Cancer Sci. 2005 Jul.

Abstract

Aberrant DNA methylation has been shown to play an important role during multistage carcinogenesis in various human organs. The aim of the present study was to evaluate the significance of DNA methyltransferase 1 (DNMT1) protein expression during pancreatic carcinogenesis. Immunohistochemical analysis of DNMT1 in 48 peripheral pancreatic duct epithelia showing no remarkable histological findings without an inflammatory background (DE), 54 peripheral pancreatic duct epithelia with an inflammatory background (DEI), 188 pancreatic intraepithelial neoplasias (PanIN), and 220 areas of invasive ductal carcinoma from surgical specimens resected from 100 patients, was carried out. The average incidence of DNMT1 immunoreactivity increased progressively from DE to DEI (P = 0.003), from DE and DEI to PanIN (P < 0.0001), among PanIN with different grades of dysplasia (from PanIN I to PanIN II, P = 0.0012), from PanIN to invasive ductal carcinomas (P < 0.0001) and among invasive ductal carcinomas with different grades of histological differentiation (from well or moderately to poorly differentiated adenocarcinomas, P < 0.0001). High-level DNMT1 protein expression in invasive ductal carcinomas was correlated significantly with an advanced t category (P = 0.0224) and an advanced stage (P = 0.0294). Moreover, patients with invasive ductal carcinomas showing high-level DNMT1 protein expression had a poorer outcome (P = 0.0469). These data suggest that increased DNMT1 protein expression participates in multistage pancreatic carcinogenesis from the precancerous stage to malignant progression of ductal carcinomas and may be a biological predictor of poor prognosis.

PubMed Disclaimer

Figures

Figure 1

Immunohistochemical examination for DNA methyltransferase 1 (DNMT1) in tissue specimens. No detectable DNMT1 immunoreactivity was observed in peripheral pancreatic duct epithelia showing no remarkable histological findings without an inflammatory background (a). However, scattered DNMT1‐positive cells were observed in peripheral duct epithelia with an inflammatory background accompanied by pancreatic acinar atrophy (b). In panel (b), infiltrating lymphocytes as internal controls show positive immunoreactivity for DNMT1 (*). The incidence of DNMT1 immunoreactivity increased progressively from pancreatic intraepithelial neoplasia (PanIN) IB (c), PanIN II (d), moderately differentiated adenocarcinoma (e), to poorly differentiated adenocarcinoma (f). ×200

Figure 2

Heterogeneity of DNA methyltransferase 1 (DNMT1) protein expression among components showing different grades of histological differentiation in a representative cancer from a single patient. Moderately (b) and poorly (c) differentiated adenocarcinoma components showed a higher incidence of DNMT1 immunoreactivity than the well‐differentiated adenocarcinoma component (a).

Figure 3

A summary of the incidence of DNA methyltransferase 1 (DNMT1) immunoreactivity in precancerous conditions and ductal carcinomas of the pancreas. Immunohistochemical examination was performed. For each sample (n = 510) at least 500 cells were randomly counted. The incidence of DNMT1 immunoreactivity in each sample was expressed as a percentage of all the cells counted. A progressive increase in the incidence of DNMT1 immunoreactivity was observed during multistage pancreatic carcinogenesis. The error bars represent standard deviation. DE, peripheral pancreatic duct epithelia showing no remarkable histological findings without an inflammatory background; DEI, peripheral pancreatic duct epithelia with an inflammatory background; PanIN, pancreatic intraepithelial neoplasia; WD, well‐differentiated adenocarcinoma; MD, moderately differentiated adenocarcinoma; PD, poorly differentiated adenocarcinoma.

Figure 4

Kaplan–Meier survival curve. Immunohistochemical examination was performed. For each patient who underwent curative resection by partial pancreatoduodenectomy or distal pancreatectomy (n = 74), the level of DNA methyltransferase 1 (DNMT1) protein expression in the cancer was considered to be low if less than 20% of the cancer cells showed DNMT1 immunoreactivity, and high if 20% or more of the cancer cells were positive for DNMT1 after a thorough evaluation of two or three representative tissue sections. The patients with a high level of DNMT1 protein expression (n = 37) had a poorer prognosis than those with a low level (n = 37) (P = 0.0469, log rank test).

References

1. Jemal A, Murray T, Samuels A, Ghafoor A, Ward E, Thun MJ. Cancer statistics, 2003. CA Cancer J Clin 2003; 53: 5–26. - PubMed
1. Matsuno SM, Egawa S, Fukuyama S et al. Pancreatic cancer registry in Japan: 20 years of experience. Pancreas 2004; 28: 219–30. - PubMed
1. Howes N, Neoptolemos JP. Risk of pancreatic ductal adenocarcinoma in chronic pancreatitis. Gut 2002; 51: 765–6. - PMC - PubMed
1. Hruban RH, Adsay NV, Albores‐Saavedra J et al. Pancreatic intraepithelial neoplasia: a new nomenclature and classification system for pancreatic duct lesions. Am J Surg Pathol 2001; 25: 579–86. - PubMed
1. Hruban RH, Goggins M, Parsons J, Kern SE. Progression model for pancreatic cancer. Clin Cancer Res 2000; 6: 2969–72. - PubMed

Increased DNA methyltransferase 1 (DNMT1) protein expression in precancerous conditions and ductal carcinomas of the pancreas - PubMed (original) (raw)