Alvarez Hector, Corvalan Alejandro, Roa Juan C, Argani Pedram, Murillo Francisco, Edwards Jennifer, Beaty Robert, Feldmann Georg, Hong Seung-Mo, Mullendore Michael, Roa Ivan, Ibañez Luis, Pimentel Fernando, Diaz Alfonso, Riggins Gregory J, Maitra Anirban
Department of Pathology, Pontificia Universidad Católica de Chile, Santiago, Chile.
Clin Cancer Res. 2008 May 1;14(9):2631-8. doi: 10.1158/1078-0432.CCR-07-1991.
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.
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.
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).
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.
胆囊癌（GBC）在美国是一种不常见的肿瘤，但死亡率很高。这种恶性肿瘤在分子水平上仍 largely 未被充分研究，以至于几乎没有靶向治疗方法或预测性生物标志物。
我们构建了首个由 21 个碱基对的长 SAGE 标签组成的来自 GBC 和非肿瘤性胆囊黏膜的基因表达序列分析（SAGE）文库系列。SAGE 文库来自三名分期匹配的 GBC 患者（分别代表西班牙裔/拉丁裔、美洲原住民和白种人种族）以及一个组织学上无结石的胆囊。对来自五对匹配的 GBC 和相应非肿瘤性胆囊黏膜的显微切割上皮进行实时定量 PCR。以高通量组织微阵列形式对 182 个存档的 GBC 进行免疫组织化学分析。
在 GBC 的所有成对比较中，与结缔组织生长因子（CTGF）转录本相对应的 SAGE 标签被鉴定为差异过度表达（P < 0.001）。实时定量 PCR 证实，与非肿瘤性胆囊上皮相比，显微切割的原发性 GBC 中 CTGF 转录本有显著过度表达（P < 0.05），但转移性 GBC 中没有。通过免疫组织化学，182 个 GBC 中有 66 个（36%）具有高 CTGF 抗原标记，在单变量分析中这与更好的生存率显著相关（P = 0.0069，对数秩检验）。
通过 SAGE 对 GBC 转录组进行的无偏分析已将 CTGF 表达鉴定为这种恶性肿瘤中预后良好的预测性生物标志物。来自 GBC 和非肿瘤性胆囊黏膜的 SAGE 文库可在癌症基因组解剖计划网站上公开获取，应有助于对这种致命肿瘤进行急需的研究。
