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Overexpression of p21^WAF1/CIP1 is an Early Event in the Development of Pancreatic Intraepithelial Neoplasia¹

Cancer Research Program, Garvan Institute of Medical Research, St. Vincent’s Hospital, Darlinghurst, NSW 2010 Australia [A. V. B., J. G. K., D. R. H., S. M. H., R. L. S.]; Institute of Clinical Pathology and Medical Research, Westmead Hospital, Westmead, NSW 2140, Australia [J. G. K., S. A. B.]; Department of Anatomical Pathology, Royal Prince Alfred Hospital, and Department of Pathology, University of Sydney, Camperdown, NSW 2050, Australia [C-S. L.]; and Division of Surgery [A. V. B., T. B. H.] and Department of Anatomical Pathology (A. L. M.), St. Vincent’s Hospital Campus, Darlinghurst, NSW 2010, Australia

Pancreatic cancer (PC) is thought to develop through a series of duct lesions termed pancreatic intraepithelial neoplasia (PanIN). Characterization of the molecular pathology of these lesions may lead to additional understanding of pancreatic ductal carcinogenesis. We examined the protein expression of four functionally related genes, p21^WAF1/CIP1 (CDKN1A), p53, cyclin D1 (CCND1), and DPC4/Smad4 (MADH4), aberrations of which are associated with PC, within 451 PanIN lesions present in the pancreata of 60 patients. p21^WAF1/CIP1 overexpression was present in the normal ducts of 9% of patients and increased progressively to 16% of patients with PanIN-1A lesions, to 32% of patients with PanIN-1B lesions, 56% of patients with PanIN-2 lesions, 80% of patients with PanIN-3 lesions, and 85% of patients with invasive carcinomas (P < 0.01). p53 and cyclin D1 overexpression occurred predominantly in PanIN-3 lesions (P < 0.01), and loss of DPC4/Smad4 expression occurred predominantly in PanIN-3 lesions and invasive carcinoma (P < 0.01). In addition, p21^WAF1/CIP1 overexpression occurred independently of p53 and DPC4/Smad4 expression within invasive carcinoma and PanIN-3 lesions. Cyclin D1 overexpression or loss of DPC4/Smad4 expression was apparent in 85% of invasive carcinomas but in only 14% of PanIN-2 lesions. These data demonstrate that overexpression of p21^WAF1/CIP1 occurs early in the development of PanIN, before aberrations in p53, cyclin D1, and DPC4/Smad4 expression. p21^WAF1/CIP1 overexpression, independent of p53 and/or DPC4/Smad4 expression, may reflect increased Ras activity, either directly through activating K-ras mutations or as a consequence of HER-2/neu (ERBB2) overexpression, both of which are common in PC and in early events in the development of PanIN. These data support further the current progression model for PC and demonstrate that aberrant expression of key cell cycle regulatory genes may be important in the early development and progression of PanIN.

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