Sanford Thomas, Porten Sima, Meng Maxwell V
Department of Urology, University of California San Francisco, San Francisco, California, United States of America.
PLoS One. 2015 Aug 28;10(8):e0137141. doi: 10.1371/journal.pone.0137141. eCollection 2015.
Prior studies have shown genetic similarities between upper tract and bladder urothelial carcinoma. However, upper tract urothelial carcinoma tends to be higher grade than bladder urothelial carcinoma and tends to form in patients with certain familial conditions (e.g. Lynch Syndrome), indicating there may be unique biologic processes in these tumors. The purpose of this study was to evaluate the differences in gene expression between upper tract and bladder urothelial carcinoma using microarray data.
DESIGN, SETTING, PARTICIPANTS: A search of publicly available microarray datasets identified a clinically annotated dataset of 12 upper tract and 20 bladder urothelial carcinoma specimens. Gene expression analysis of data derived from the Affymetrix HGU133Plus2 chip was performed. Bioconductor packages were used to evaluate clustering, differential gene expression, pathways relevant to oncology, and a basal/luminal signature in upper tract versus bladder urothelial carcinoma.
When separated by pathologic T stage, there was evidence of differential clustering among pT3 tumors and significant gene expression differences in 81 genes. Pathway analysis revealed differences in HGF and TNF signaling pathways. Upper tract tumors tended to have high expression of genes associated with a luminal subtype. One of the genes most highly expressed in upper tract tumors, SLITRK6, is the target of an antibody drug conjugate (AGS15E) currently in phase I clinical trials.
This study provides evidence for molecular differences between upper tract and bladder urothelial carcinoma, some of which contribute to oncologic-relevant pathways. Upper tract tumors tended to express genes consistent with a luminal subtype. We also identify a marker, SLITRK6, as a potential target for patients with advanced upper tract urothelial carcinoma.
先前的研究表明上尿路尿路上皮癌与膀胱尿路上皮癌之间存在遗传相似性。然而，上尿路尿路上皮癌往往比膀胱尿路上皮癌分级更高，且倾向于在某些家族性疾病（如林奇综合征）患者中发生，这表明这些肿瘤可能存在独特的生物学过程。本研究的目的是利用微阵列数据评估上尿路尿路上皮癌与膀胱尿路上皮癌之间的基因表达差异。
设计、背景、参与者：对公开可用的微阵列数据集进行搜索，确定了一个包含12例上尿路尿路上皮癌和20例膀胱尿路上皮癌标本的临床注释数据集。对来自Affymetrix HGU133Plus2芯片的数据进行基因表达分析。使用生物导体软件包评估聚类、差异基因表达、与肿瘤学相关的通路以及上尿路尿路上皮癌与膀胱尿路上皮癌之间的基底/腔面特征。
按病理T分期分开时，有证据表明pT3肿瘤之间存在差异聚类，且81个基因存在显著的基因表达差异。通路分析揭示了HGF和TNF信号通路的差异。上尿路肿瘤倾向于高表达与腔面亚型相关的基因。在上尿路肿瘤中表达最高的基因之一SLITRK6，是目前处于I期临床试验阶段的一种抗体药物偶联物（AGS15E）的靶点。
本研究为上尿路尿路上皮癌与膀胱尿路上皮癌之间的分子差异提供了证据，其中一些差异与肿瘤相关通路有关。上尿路肿瘤倾向于表达与腔面亚型一致的基因。我们还确定了一个标志物SLITRK6，作为晚期上尿路尿路上皮癌患者的潜在靶点。
