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

Objectives: 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.

Methods: 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.

Results: 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.

Conclusions: 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.