title: Regional differences in gallbladder cancer pathogenesis: insights from a comparison of cell cycle-regulatory, PI3K, and pro-angiogenic protein expression.
abstract: BACKGROUND
  The variable incidence of gallbladder cancer (GBCA) suggests regional pathogenetic differences. This study compares cell cycle-regulatory, angiogenesis-related, and PI3K pathway protein expression in GBCAs from three continents.
  
  
  METHODS
  Immunohistochemical expression of several proteins was assessed, correlated with clinicopathologic variables, and compared among centers from Chile (Fundación Arturo López Pérez [FALP]), Japan (Yokohama City University [YCU]), and the United States (Memorial Sloan-Kettering Cancer Center [MSKCC]). Hierarchical clustering was used to partition the data based on protein-expression and treatment center.
  
  
  RESULTS
  Tissue from 117 patients (MSKCC = 76; FALP = 22; YCU = 19) was analyzed. Mdm2 overexpression was seen only at MSKCC (p < 0.0001). Absence of p21 (p = 0.03) and VEGFR2 (p = 0.018) were more common and p27 expression was less frequent (p = 0.047) in tumors from YCU. Ki-67 labeling index in YCU tumors (median = 10) was two-thirds lower than at other centers. On hierarchical clustering analysis, all YCU patients (p = 0.017) and those with early tumors (p = 0.017) clustered separately from MSKCC. Median disease-specific survival after curative intent (R0) resection was 27 months and was similar among centers (p = 0.9). Median disease-specific survival of patients with early tumors was 28.4 months and was higher at YCU (not reached, p = 0.06).
  
  
  CONCLUSIONS
  Cell cycle-regulatory protein expression patterns of YCU tumors differed from those treated at FALP and MSKCC. The differential clustering of protein expression and survival in patients with early tumors suggest regional differences in pathogenesis and disease biology.
authors.affiliation: Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, NY, USA.
authors.forename: Jean M
authors.initials: JM
authors.lastname: Butte
authors.forename: Javiera
authors.initials: J
authors.lastname: Torres
authors.forename: Emanuela F
authors.initials: EF
authors.lastname: Veras
authors.forename: Kenichi
authors.initials: K
authors.lastname: Matsuo
authors.forename: Mithat
authors.initials: M
authors.lastname: Gönen
authors.forename: Michael I
authors.initials: MI
authors.lastname: D'Angelica
authors.forename: Enrique
authors.initials: E
authors.lastname: Waugh
authors.forename: Manuel
authors.initials: M
authors.lastname: Meneses
authors.forename: Yoshiyaki
authors.initials: Y
authors.lastname: Inayama
authors.forename: Yuman
authors.initials: Y
authors.lastname: Fong
authors.forename: Ronald P
authors.initials: RP
authors.lastname: Dematteo
authors.forename: Hernan
authors.initials: H
authors.lastname: De La Fuente
authors.forename: Itaru
authors.initials: I
authors.lastname: Endo
authors.forename: David S
authors.initials: DS
authors.lastname: Klimstra
authors.forename: William R
authors.initials: WR
authors.lastname: Jarnagin
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002677:Chile; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D005260:Female; D005706:Gallbladder Neoplasms / Q000378:metabolism* / Q000473:pathology* / Q000601:surgery; D006801:Humans; D007564:Japan; D053208:Kaplan-Meier Estimate; D019394:Ki-67 Antigen / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D009367:Neoplasm Staging; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism; D051736:Proto-Oncogene Proteins c-mdm2 / Q000378:metabolism; D014481:United States; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism
chemical_list: C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D019394:Ki-67 Antigen; D018809:Proliferating Cell Nuclear Antigen; C413374:p27 antigen; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2; D040301:Vascular Endothelial Growth Factor Receptor-2