Wild Peter J, Herr Alexander, Wissmann Christoph, Stoehr Robert, Rosenthal Andre, Zaak Dirk, Simon Ronald, Knuechel Ruth, Pilarsky Christian, Hartmann Arndt
Institute of Pathology, University of Regensburg, Regensburg, Germany.
Clin Cancer Res. 2005 Jun 15;11(12):4415-29. doi: 10.1158/1078-0432.CCR-05-0259.
The aim of the present study was to define gene expression profiles of noninvasive and invasive bladder cancer, to identify potential therapeutic or screening targets in bladder cancer, and to define genetic changes relevant for tumor progression of recurrent papillary bladder cancer (pTa).
Overall, 67 bladder neoplasms (46 pTa, 3 pTis, 10 pT1, and 8 pT2) and eight normal bladder specimens were investigated by a combination of laser microdissection and gene expression profiling. Eight of 16 patients with recurrent noninvasive papillary bladder tumors developed carcinoma in situ (pTis) or invasive bladder cancer (> or = pT1G2) in the course of time. RNA expression results of the putative progression marker cathepsin E (CTSE) were confirmed by immunohistochemistry using high-throughput tissue microarray analysis (n = 776). Univariate analysis of factors regarding overall survival, progression-free survival, and recurrence-free survival in patients with urothelial bladder cancer was done.
Hierarchical cluster analyses revealed no differences between pTaG1 and pTaG2 tumors. However, distinct groups of invasive cancers with different gene expression profiles in papillary and solid tumors were found. Progression-associated gene profiles could be defined (e.g., FABP4 and CTSE) and were already present in the preceding noninvasive papillary tumors. CTSE expression (P = 0.003) and a high Ki-67 labeling index of at least 5% (P = 0.01) were the only factors that correlated significantly with progression-free survival of pTa tumors in our gene expression approach.
Gene expression profiling revealed novel genes with potential clinical utility to select patients that are more likely to develop aggressive disease.
本研究旨在确定非侵袭性和侵袭性膀胱癌的基因表达谱，识别膀胱癌潜在的治疗或筛查靶点，并确定与复发性乳头状膀胱癌（pTa）肿瘤进展相关的基因变化。
总体而言，通过激光显微切割和基因表达谱分析相结合的方法，对67例膀胱肿瘤（46例pTa、3例pTis、10例pT1和8例pT2）以及8例正常膀胱标本进行了研究。16例复发性非侵袭性乳头状膀胱肿瘤患者中有8例在病程中发展为原位癌（pTis）或侵袭性膀胱癌（≥pT1G2）。使用高通量组织微阵列分析（n = 776）通过免疫组织化学证实了假定的进展标志物组织蛋白酶E（CTSE）的RNA表达结果。对尿路上皮膀胱癌患者的总生存、无进展生存和无复发生存的相关因素进行了单变量分析。
层次聚类分析显示pTaG1和pTaG2肿瘤之间无差异。然而，在乳头状和实体肿瘤中发现了具有不同基因表达谱的不同侵袭性癌组。可以定义进展相关的基因谱（例如，FABP4和CTSE），并且这些基因谱已经存在于先前的非侵袭性乳头状肿瘤中。在我们的基因表达方法中，CTSE表达（P = 0.003）和至少5%的高Ki-67标记指数（P = 0.01）是与pTa肿瘤无进展生存显著相关的唯一因素。
基因表达谱分析揭示了具有潜在临床应用价值的新基因，可用于选择更有可能发展为侵袭性疾病的患者。
