Bi-allelic inactivation of TCF1 in hepatic adenomas

Abstract

Liver adenomas are benign tumors at risk of malignant transformation. In a genome-wide search for loss of heterozygosity (LOH) associated with liver adenomas, we found a deletion in chromosome 12q in five of ten adenomas. In most cases, LOH at 12q was the only recurrent genetic alteration observed, suggesting the presence of a tumor-suppressor gene in that region. A minimal common region of deletion was defined in 12q24 that included the gene TCF1 (transcription factor 1), encoding hepatocyte nuclear factor 1 (HNF1; refs 1,2). Heterozygous germline mutations of TCF1 have been identified in individuals affected with maturity-onset diabetes of the young type 3 (MODY3; ref. 3). Bi-allelic inactivation of TCF1 was found in 10 of 16 screened adenomas, and heterozygous germline mutation were present in three affected individuals. Furthermore, 2 well-differentiated hepatocellular carcinomas (HCCs) occurring in normal liver contained somatic bi-allelic mutations of 30 screened HCCs. These results indicate that inactivation of TCF1, whether sporadic or associated with MODY3, is an important genetic event in the occurrence of human liver adenoma, and may be an early step in the development of some HCCs.

Malignant transformation of hepatic adenomas

“…2 Interestingly, either of these two mutations are seen in about 50% of all adenomas, yet are generally mutually exclusive. 5 Those adenomas with b-catenin mutations have been reported to have large deletions in about one-half of the cases and mutations in exon 3 in the remaining half of cases.…”

“…The vast majority of hepatic adenomas have been reported in one of three clinical settings: (1) most commonly in reproductive age women with a history of oral contraceptive pill therapy, (2) rarely in individuals with a history of excess androgen exposure, such as androgen steroid therapy for Fanconi's anemia, and (3) also occasionally in glycogen storage disease types I and III. Rare cases of hepatic adenomas have also been reported in a number of other diverse clinical settings.…”

“…1 The association of hepatic adenomas with different risk factors suggests that they may be a heterogeneous group at the molecular level. To date, mutations in the TCF1 gene (also known as HNF1-a) 2 as well as dysregulation of the b-catenin pathway 3,4 have been the best characterized molecular lesions in these tumors, and, in fact, appear to be mutually exclusive in most cases. For hepatic adenomas with TCF1 mutations, the adenomas are more likely to show significant fatty change and are less likely to be associated with cytological atypia or malignant changes.…”

Genetics of hepatocellular tumors

“…Specific genetic alterations associated with liver cell adenomas Recently, biallelic mutation of the transcription factor 1 (TCF1) gene, coding for hepatocyte nuclear factor 1a (HNF1a), were identified in 60% of a sample of liver cell adenoma cases (Bluteau et al, 2002b) (Figure 1). Hepatocyte nuclear factor 1a is a transcription factor that is implicated in hepatocyte differentiation and is required for the liver-specific expression of several genes, including b-fibrinogen, albumin and a1-antitrypsin (Frain et al, 1989;Baumhueter et al, 1990;Cereghini et al, 1990;Chouard et al, 1990).…”

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

“…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.…”