Downregulation of HNF-1B in Renal Cell Carcinoma Is Associated With Tumor Progression and Poor Prognosis

Abstract

The aim of this study was to identify new prognostic factors in metastatic renal cell carcinoma (RCC) based on the analysis of precisely defined metastatic tissue. Expression profiling was done on 26 snap-frozen samples of clear-cell RCC metastases with complete follow-up (up to 116 months) using laser microdissection and oligonucleotide microarrays (Affymetrix). A prognosis-associated gene signature was determined using the semi-supervised principal components analysis method. Validation was performed with quantitative RT-PCR on samples of normal renal tissue (n = 6), RCC primary tumor (n = 57), and RCC metastases (n = 59). Immunohistochemistry (IHC) was done to localize HNF-1B. Analysis of expression data revealed a three-gene signature consisting of HNF-1B, KIAA1919, and SYDE1, which discriminated well between 2 prognosis groups (P < .05), independently of the TNMG classification. Expression of HNF-1B was analyzed in detail. HNF-1B mRNA expression correlated with malignant transformation and progression (normal renal tissue > primary tumor > metastasis; P < .0001). There was a significant correlation between high HNF-1B mRNA expression in primary tumor and better prognosis (P < .05). IHC showed a specific nuclear HNF-1B staining confined to the tumor cells of the primary tumors and of the metastases. The level of HNF-1B mRNA expression significantly decreases with tumor progression, and patients with high HNF-1B mRNA levels have a significantly better prognosis. HNF-1B might be a useful prognostic factor for metastatic RCC and also a potential therapeutic target in the future.