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Human Molecular Genetics Advance Access published online on January 13, 2005
Human Molecular Genetics, doi:10.1093/hmg/ddi057
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Human Molecular Genetics © Oxford University Press 2005; all rights reserved

Article

Germline Hepatocyte Nuclear Factor 1{alpha} and 1ß mutations in renal cell carcinomas

Sandra Rebouissou 1, Viorel Vasiliu 2, Cristel Thomas 1, Christine Bellanné-Chantelot 3, Hung Bui 4, Yves Chrétien 5, José Timsit 6, Christophe Rosty 7, Pierre Laurent-Puig 8, Dominique Chauveau 9, and Jessica Zucman-Rossi 10*

1 Inserm U434, CEPH, IUH Saint-Louis, Paris, France
2 Service d'Anatomopathologie, Hôpital Necker, AP-HP, Paris, France
3 Laboratoire de Génétique et Biologie Moléculaire, Hôpital Saint-Antoine, AP-HP, Paris, France
4 CEPH, Fondation Jean Dausset, Paris, France
5 Service d'Urologie, Hôpital Necker, AP-HP, Paris, France
6 Service d'Endocrinologie, Hôpital Cochin, AP-HP, Paris, France
7 Service de pathologie, Institut Curie, Paris, France
8 Inserm U490, Paris, France
9 Service de Néphrologie et Inserm U507, Hôpital Necker, AP-HP, Paris France
10 Inserm U434, CEPH, IUH Paris Saint-Louis, 27 rue Juliette Dodu, 75010 Paris

* To whom correspondence should be addressed.
Jessica Zucman-Rossi, E-mail: zucman{at}cephb.fr


  Abstract

Mutations in one copy of the hepatocyte nuclear factors (HNF) 1{alpha} and 1ß homeodomain containing transcription factors predispose the carrier to maturity-onset diabetes of the young (MODY) type 3 and 5. Moreover, previous identification of biallelic inactivation of HNF1{alpha} 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 HNF1ß and HNF1{alpha} inactivation in a series of 20 ovarian and 35 renal neoplasms. Biallelic HNF1ß 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 HNF1ß, was turned off. Interestingly, in two of 13 clear cell renal carcinomas, we found a monoallelic germline mutation of HNF1{alpha} 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 HNF1ß, PKHD1 and UMOD in a first group and associating HNF1{alpha}, HNF4{alpha}, FABP1 and UGT2B7 in a second group. Finally, these results suggest that germline mutations of HNF1ß and HNF1{alpha} may predispose to renal tumors. Furthermore, we suggest that HNF1ß functions as a tumor suppressor gene in chromophobe renal cell carcinogenesis through a PKHD1 expression control.


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