title: Role for p16(INK4a) in progression of gastrointestinal stromal tumors of the stomach: alteration of p16(INK4a) network members.
abstract: Gastrointestinal stromal tumors feature a wide spectrum of biologic behavior, ranging from benign to extremely malignant. To determine the role of p16(INK4a) alteration in progression of gastrointestinal stromal tumors of the stomach, we have investigated protein expression and gene methylation in correlation with clinicopathologic factors and survival. In addition to immunohistochemical analysis of p16(INK4a) in a series of 95 cases, real-time quantitative methylation specific polymerase chain reaction for p16(INK4a) and immunostaining for cyclin D1, cyclin E, pRb, DP-1, E2F-1, and Ki-67 were also evaluated in randomly selected samples. The p16(INK4a) labeling indices ranged from 0% to 74% (median, 21%), demonstrating a significant inverse correlation with size (P = .046). On univariate (P = .003) and multivariate (P = .067) analyses, loss of p16(INK4a) expression increased the likelihood of a poor tumor-related survival. In addition, size (P = .036) and the mitotic index (P = .005) had independent prognostic influence. The p16(INK4a) methylation index, which ranged from 0% to 100% (median, 17%), was significantly higher in larger tumors (P < .001) and in high-risk category lesions (P = .001) and inversely correlated with protein expression. Hierarchical cluster analysis based on expression of p16(INK4a) network members identified 2 clusters in 27 randomly selected tumor samples, containing 11 and 16 tumors each. Former cluster samples demonstrated higher risk category (P = .022), higher p16(INK4a) methylation (P < .001), and more reduced pRb expression (P < .018). In addition, p16(INK4a) network members clustered into 2 groups: (1) showing down-regulated p16(INK4a) protein and up-regulating of both cyclin D1 and DP-1 and (2) down-regulated pRb and up-regulated E2F-1. We conclude that p16(INK4a) alteration has an important role in progression of gastrointestinal stromal tumors of the stomach. Furthermore, the study provides a possible link between regulation of p16(INK4a) network members and gastrointestinal stromal tumors.
authors.affiliation: Department of Human Pathology, Juntendo University School of Medicine, Bunkyo-ku, Tokyo 113-8421, Japan. hmitomi@juntendo-ac.jp
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Mitomi
authors.forename: Naoshi
authors.initials: N
authors.lastname: Fukui
authors.forename: Ichiro
authors.initials: I
authors.lastname: Kishimoto
authors.forename: Satoshi
authors.initials: S
authors.lastname: Tanabe
authors.forename: Shiro
authors.initials: S
authors.lastname: Kikuchi
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Saito
authors.forename: Takuo
authors.initials: T
authors.lastname: Hayashi
authors.forename: Takashi
authors.initials: T
authors.lastname: Yao
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000704:Analysis of Variance; D016000:Cluster Analysis; D056741:Cyclin D / Q000378:metabolism; D019927:Cyclin E / Q000378:metabolism; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000378:metabolism*; D050687:E2F1 Transcription Factor / Q000378:metabolism; D005260:Female; D046152:Gastrointestinal Stromal Tumors / Q000175:diagnosis / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D008297:Male; D008745:Methylation; D008875:Middle Aged; D011379:Prognosis; D016160:Retinoblastoma Protein / Q000378:metabolism; D012189:Retrospective Studies; D018570:Risk Assessment; D013274:Stomach Neoplasms / Q000175:diagnosis / Q000378:metabolism* / Q000473:pathology; D050680:Transcription Factor DP1 / Q000378:metabolism; D055815:Young Adult
chemical_list: D056741:Cyclin D; D019927:Cyclin E; D019941:Cyclin-Dependent Kinase Inhibitor p16; D050687:E2F1 Transcription Factor; D016160:Retinoblastoma Protein; C493735:TFDP1 protein, human; D050680:Transcription Factor DP1