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Serial Analysis of Gene Expression Identifies Connective Tissue Growth Factor Expression as a Prognostic Biomarker in Gallbladder Cancer

Authors' Affiliations: Departments of ¹ Pathology and ² Surgery, Pontificia Universidad Católica de Chile, Santiago, Chile; ³ Department of Pathology, Universidad de la Frontera, Temuco, Chile; ⁴ Department of Surgery, Hospital Sótero del Rio, Santiago Chile; and Departments of ⁵ Pathology, ⁶ Neurosurgery, and ⁷ Oncology, and ⁸ McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland

Requests for reprints: Anirban Maitra, Johns Hopkins University School of Medicine, CRB II, Room 345, 1550 Orleans Street, Baltimore, MD 21231. Phone: 410-955-3511; Fax: 410-614-0671; E-mail: Amaitra1{at}jhmi.edu or Gregory J. Riggins, Johns Hopkins University School of Medicine, CRB II, Room 257, 1550 Orleans Street, Baltimore, MD 21231. E-mail: Griggin1{at}jhmi.edu.

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.

Experimental Design: 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.