Germline hepatocyte nuclear factor 1α and 1β mutations in renal cell carcinomas

Abstract

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.

Epigenetic inactivation of TCF2 in ovarian cancer and various cancer cell lines

“…The Methylation of TCF2 was cancer-specific and, together with histone deacetylation, may be involved in tumorigenesis in a subset of ovarian cancers. It has been reported that patients with germ line mutation of TCF2 develop renal tumours (BellanneChantelot et al, 2004), and TCF2 mutations have been identified in renal cell cancer (Rebouissou et al, 2005). On the other hand, no TCF2 mutation has been previously observed in ovarian cancer (Rebouissou et al, 2005), which is consistent with our present finding that TCF2 is not mutated in ovarian cancer.…”

“…It has been reported that patients with germ line mutation of TCF2 develop renal tumours (BellanneChantelot et al, 2004), and TCF2 mutations have been identified in renal cell cancer (Rebouissou et al, 2005). On the other hand, no TCF2 mutation has been previously observed in ovarian cancer (Rebouissou et al, 2005), which is consistent with our present finding that TCF2 is not mutated in ovarian cancer. Apparently, TCF2 expression is silenced by an epigenetic rather than genetic mechanism.…”

“…The specific role of TCF2 methylation in the development and progression of ovarian cancer remains unknown, but TCF2 mutations are known to affect expression of downstream genes such as HNF4a, PKHD1 and UMOD Rebouissou et al, 2005). We showed expression of HNF4a to be well correlated with that of TCF2 and to be upregulated by inducing TCF2 expression using a methyltransferase inhibitor, which suggests alterations in the hepatocyte nuclear factor network can be reversed by inducing TCF2 through demethylation of the gene.…”

“…For instance, TCF2 defects cause developmental abnormalities in multiple tissues, including kidney and pancreas (Horikawa et al, 1997;Haumaitre et al, 2005), and Bluteau et al (2002) identified biallelic mutations of TCF1 in hepatic adenomas (Bluteau et al, 2002). Subsequently, mutations of TCF1 also were found in colorectal cancer with MSI (Laurent-Puig et al, 2003) and endometrial tumours (Rebouissou et al, 2004), while Rebouissou et al (2005) also identified mutations of TCF2 in renal carcinomas.…”

Mutations in BHD and TP53 genes, but not in HNF1β gene, in a large series of sporadic chromophobe renal cell carcinoma

“…The HNF1b gene (hepatocyte nuclear factor), which was found mutated in patients with maturity-onset diabetes of the young (MODY5), is located at 17q12 (Horikawa et al, 1997). Biallelic inactivation of this gene has been reported in two of 12 patients with chromophobe RCC; both patients have germline HNF1b mutations, and their tumours showed LOH, suggesting inactivation through the classic two-hit hypothesis (Rebouissou et al, 2005).…”