title: Serial analysis of gene expression identifies connective tissue growth factor expression as a prognostic biomarker in gallbladder cancer.
abstract: BACKGROUND
  Gallbladder cancer (GBC) is an uncommon neoplasm in the United States, but one with high mortality rates. This malignancy remains largely understudied at the molecular level such that few targeted therapies or predictive biomarkers exist.
  
  
  METHODS
  We built the first series of serial analysis of gene expression (SAGE) libraries from GBC and nonneoplastic gallbladder mucosa, composed of 21-bp long-SAGE tags. SAGE libraries were generated from three stage-matched GBC patients (representing Hispanic/Latino, Native American, and Caucasian ethnicities, respectively) and one histologically alithiasic gallbladder. Real-time quantitative PCR was done on microdissected epithelium from five matched GBC and corresponding nonneoplastic gallbladder mucosa. Immunohistochemical analysis was done on a panel of 182 archival GBC in high-throughput tissue microarray format.
  
  
  RESULTS
  SAGE tags corresponding to connective tissue growth factor (CTGF) transcripts were identified as differentially overexpressed in all pairwise comparisons of GBC (P < 0.001). Real-time quantitative PCR confirmed significant overexpression of CTGF transcripts in microdissected primary GBC (P < 0.05), but not in metastatic GBC, compared with nonneoplastic gallbladder epithelium. By immunohistochemistry, 66 of 182 (36%) GBC had high CTGF antigen labeling, which was significantly associated with better survival on univariate analysis (P = 0.0069, log-rank test).
  
  
  CONCLUSIONS
  An unbiased analysis of the GBC transcriptome by SAGE has identified CTGF expression as a predictive biomarker of favorable prognosis in this malignancy. The SAGE libraries from GBC and nonneoplastic gallbladder mucosa are publicly available at the Cancer Genome Anatomy Project web site and should facilitate much needed research into this lethal neoplasm.
authors.affiliation: Department of Pathology, Pontificia Universidad Católica de Chile, Santiago, Chile.
authors.forename: Hector
authors.initials: H
authors.lastname: Alvarez
authors.forename: Alejandro
authors.initials: A
authors.lastname: Corvalan
authors.forename: Juan C
authors.initials: JC
authors.lastname: Roa
authors.forename: Pedram
authors.initials: P
authors.lastname: Argani
authors.forename: Francisco
authors.initials: F
authors.lastname: Murillo
authors.forename: Jennifer
authors.initials: J
authors.lastname: Edwards
authors.forename: Robert
authors.initials: R
authors.lastname: Beaty
authors.forename: Georg
authors.initials: G
authors.lastname: Feldmann
authors.forename: Seung-Mo
authors.initials: SM
authors.lastname: Hong
authors.forename: Michael
authors.initials: M
authors.lastname: Mullendore
authors.forename: Ivan
authors.initials: I
authors.lastname: Roa
authors.forename: Luis
authors.initials: L
authors.lastname: Ibañez
authors.forename: Fernando
authors.initials: F
authors.lastname: Pimentel
authors.forename: Alfonso
authors.initials: A
authors.lastname: Diaz
authors.forename: Gregory J
authors.initials: GJ
authors.lastname: Riggins
authors.forename: Anirban
authors.initials: A
authors.lastname: Maitra
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000378:metabolism; D019295:Computational Biology; D055513:Connective Tissue Growth Factor; D005006:Ethnicity / Q000235:genetics; D005260:Female; D005704:Gallbladder / Q000378:metabolism; D005706:Gallbladder Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000401:mortality / Q000473:pathology; D015870:Gene Expression; D020869:Gene Expression Profiling; D006801:Humans; D017874:Immediate-Early Proteins / Q000235:genetics* / Q000378:metabolism; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics* / Q000378:metabolism; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis; D011379:Prognosis; D012044:Regression Analysis; D046888:Tissue Array Analysis
chemical_list: D014408:Biomarkers, Tumor; C526317:CCN2 protein, human; D017874:Immediate-Early Proteins; D036341:Intercellular Signaling Peptides and Proteins; D055513:Connective Tissue Growth Factor