title: Differential roles of alterations of p53, p16, and SMAD4 expression in the progression of intraductal papillary-mucinous tumors of the pancreas.
abstract: Intraductal papillary-mucinous tumors (IPMTs) of the pancreas are characterized by dilated pancreatic ducts and ductules that are lined by tall columnar mucin-producing neoplastic epithelial cells. IPMTs have been suggested to be distinct neoplasms with a less aggressive phenotype than that of conventional ductal adenocarcinomas of the pancreas. Molecular mechanisms underlying tumorigenesis of IPMTs are beginning to be characterized. Allelic losses have frequently been detected at 9p, 17p, and 18q, suggesting that inactivation of tumor suppressor genes at these loci play a role in tumorigenesis of IPMTs. Using immunohistochemistry, we analyzed 38 IPMTs, including 9 hyperplasia, 16 adenoma, and 13 carcinoma tissues, for expression of p53, Ki-67, p16, and SMAD4. Nuclear p53 expression was observed in 5 (38%) of 13 carcinoma tissues but not in hyperplasia or adenoma tissues. Partial loss of p16 expression was observed in 9 (56%) and 12 (92%) of the 16 adenoma and 13 carcinoma tissues, respectively. Partial loss of p16 expression was observed even in adenomas with mild atypia. Partial loss of SMAD4 expression was observed in 6 (38%) and 12 (92%) of the 16 adenoma and 13 carcinoma tissues, respectively. The SMAD4 negative index was significantly higher in invasive carcinomas than in non-invasive carcinomas. Our results suggest that loss of p16 is an early event and p53 alteration is a late event during the progression of IPMTs. SMAD4 inactivation appears to be an early event but also involved in invasive tumor growth. Our results suggest that these alterations accumulate during the progression of IPMTs, reflecting results of analysis of allelic losses that showed a stepwise accumulation of genetic changes during progression.
authors.affiliation: First Department of Internal Medicine, Sapporo Medical University, Chuo-ku, Japan. ssasaki@sapmed.ac.jp
authors.forename: Shigeru
authors.initials: S
authors.lastname: Sasaki
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Yamamoto
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Kaneto
authors.forename: Itaru
authors.initials: I
authors.lastname: Ozeki
authors.forename: Yasuyo
authors.initials: Y
authors.lastname: Adachi
authors.forename: Hideyasu
authors.initials: H
authors.lastname: Takagi
authors.forename: Takeshi
authors.initials: T
authors.lastname: Matsumoto
authors.forename: Hideto
authors.initials: H
authors.lastname: Itoh
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Nagakawa
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Miyakawa
authors.forename: Shunji
authors.initials: S
authors.lastname: Muraoka
authors.forename: Akira
authors.initials: A
authors.lastname: Fujinaga
authors.forename: Toshihiro
authors.initials: T
authors.lastname: Suga
authors.forename: Masaaki
authors.initials: M
authors.lastname: Satoh
authors.forename: Fumio
authors.initials: F
authors.lastname: Itoh
authors.forename: Takao
authors.initials: T
authors.lastname: Endo
authors.forename: Kohzoh
authors.initials: K
authors.lastname: Imai
mesh_terms: D002288:Adenocarcinoma, Mucinous / Q000378:metabolism* / Q000473:pathology; D000236:Adenoma / Q000378:metabolism / Q000473:pathology; D021441:Carcinoma, Pancreatic Ductal / Q000378:metabolism* / Q000473:pathology; D002291:Carcinoma, Papillary / Q000378:metabolism* / Q000473:pathology; D016022:Case-Control Studies; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000378:metabolism*; D018450:Disease Progression; D006801:Humans; D006965:Hyperplasia / Q000378:metabolism / Q000473:pathology; D007124:Immunoenzyme Techniques; D019394:Ki-67 Antigen / Q000378:metabolism; D009361:Neoplasm Invasiveness; D010179:Pancreas / Q000378:metabolism; D010190:Pancreatic Neoplasms / Q000378:metabolism* / Q000473:pathology; D051901:Smad4 Protein; D015996:Survival Rate; D015534:Trans-Activators / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
chemical_list: D019941:Cyclin-Dependent Kinase Inhibitor p16; D004268:DNA-Binding Proteins; D019394:Ki-67 Antigen; C497796:SMAD4 protein, human; D051901:Smad4 Protein; D015534:Trans-Activators; D016159:Tumor Suppressor Protein p53