Loss of HNF1 alpha function in human renal cell carcinoma: Frequent mutations in the VHL gene but not the HNF1 alpha gene

Human renal cell carcinoma (RCC) is a common malignant disease of the kidne y characterized by dedifferentiation of renal epithelial cells. Our previou s experiments showed that most RCCs have a loss of function of the tissue-s pecific transcription factor hepatocyte nuclear factor (HNF) 1 alpha. Detai led analyses of the 10 exons encoding HNF1 alpha in 32 human RCCs by single -strand conformation polymorphism analysis and direct DNA sequencing reveal ed no tumor-associated mutation, whereas with the same probes we frequently found mutations in the von Hippel-Lindau tumor suppressor gene. No mutatio n leading to loss of HNF1 alpha function was detected by analyzing the inte grity of the HNF1 alpha transcripts in the RNA derived from RCCs by the pro tein truncation test. Investigating human RCC cell lines by western blottin g and gel retardation assays showed a dramatic loss in the expression of th e tissue-specific transcription factor HNF1 alpha in eight of 10 cell lines . As the HNF1 alpha-related transcription factor HNF1 beta was expressed in all these tumor cell lines, the loss of HNF1 alpha expression was a specif ic event and was maintained in RCC cell lines. The loss of HNF1 alpha expre ssion in RCC cell lines on the RNA level was confirmed by reverse transcrip tion polymerase chain reaction. We propose that tumor-associated mutations in the HNF1 alpha gene do not occur in human RCC and that the loss of funct ion is partially due to a transcriptional inactivation of the HNF1 alpha ge ne. (C) 1999 Wiley-Liss, Inc.