Mutations in one copy of the
hepatocyte nuclear factors (
HNF) 1alpha and 1beta homeodomain containing
transcription factors predispose the carrier to
maturity-onset diabetes of the young (
MODY) types 3 and 5, respectively. Moreover, previous identification of biallelic inactivation of HNF1alpha in
hepatocellular adenoma identified its
tumor suppressor function in hepatocarcinogenesis. The seminal observation of an ovarian
carcinoma in a MODY5 patient who subsequently developed a
chromophobe renal cell carcinoma, prompted us to screen for HNF1beta and HNF1alpha inactivation in a series of 20 ovarian and 35
renal neoplasms. Biallelic HNF1beta inactivation was found in two of 12 chromophobe
renal carcinomas by association of a germline mutation and a somatic gene deletion. In these cases, the expression of PKHD1 (
polycystic kidney and hepatic disease 1) and UMOD (
Uromodulin), two genes regulated by HNF1beta, was turned off. Interestingly, in two of 13 clear cell
renal carcinomas, we found a monoallelic germline mutation of HNF1alpha with no associated suppression of target
mRNA expression. In normal and
tumor renal tissues, we showed the existence of a network of
transcription factors differentially regulated in
tumor subtypes. We identified two related clusters of co-regulated genes associating HNF1beta, PKHD1 and UMOD in the first group and HNF1alpha, HNF4alpha, FABP1 and UGT2B7 in the second group. Finally, these results suggest that germline mutations of HNF1beta and HNF1alpha may predispose to renal
tumors. Furthermore, we suggest that HNF1beta functions as a tumor suppressor gene in chromophobe renal cell
carcinogenesis through a PKHD1 expression control.