Genetic alterations in hepatocellular adenomas: recent findings and new challenges

Abstract

Hepatocellular adenomas (HA) are benign liver tumours which usually occur in young women when they have been taking oral contraceptives for more than 2 years [1]. HA are rare tumours: their estimated incidence in France is approximately one case per 100,000 women. Over the past 15 years, their incidence has seen a sustained decline in industrialised countries; this trend is probably linked to the reduction in ethinylestradiol doses in oral contraceptives. These tumours result from a benign proliferation of hepatocytes which destroy the normal architecture of the liver. They are usually hyper-vascularised. The adenomas take the form of single (more rarely multiple) nodules. The presence of more than 10 nodules in the liver of some patients has made it possible to identify a specific nosological entity: the liver adenomatosis [2]. Unlike solitary adenomas, liver adenomatosis is diagnosed in both sexes and its development does not appear to be closely linked to the use of oral contraceptives. In about 50% of cases, HA (single, multiple or in a context of adenomatosis) is asymptomatic. However, its presence may also be revealed by complications: tumour necrosis, haemorrhage due to rupture of the adenoma and exceptionally, malignant transformation into hepatocellular carcinoma (HCC) [3–7]. In some cases, the histological diagnosis of these tumours is difficult particularly for small adenomas. A differential diagnosis must be made with respect to typical and telangiectatic focal nodular hyperplasia or well-differentiated HCC [8,9]. Diagnostic difficulties concern particularly small adenomas. In addition to the typical forms of adenoma, HA may occur in the context of glycogenosis or following exposure to androgens [10,11]. Until now, little was known about the genetics of HA. In 1976, Foster et al. described a family presenting with the autosomal dominant transmission of hepatic adenomatosis co-segregating with insulin-dependent diabetes in three generations [12]. A second link between adenomatosis and diabetes was described by Chiche and collaborators [3], but these observations remained isolated, and no recurrent constitutional or somatic genetic alterations were described in patients presenting with adenoma or adenomatosis. In our laboratory, in collaboration with clinical and pathological teams, we have searched for new tumour suppressor gene which might be involved in the tumorigenesis of HA, using a positional cloning strategy based on the search for loss of heterozygosity (LOH). We allotyped 400 microsatellite markers distributed throughout the genome, comparing normal and tumour DNA in a series of 10 HA patients. This analysis revealed the rarity of LOH in HA, although recurrent chromosomal deletions were identified on the long arm of chromosome 12 in half of the cases. A minimal deletion region common to all tumours was defined, and the TCF1 gene located in this region was screened for mutations. Biallelic mutations of the TCF1 gene coding for hepatocyte nuclear factor 1a (HNF1a) were identified in 60% of cases in a series of 16 HA patients. HNF1a is a transcription factor which controls the expression of numerous liver genes. Germline heterozygous mutations of this gene were demonstrated in 1996 by Yamagata et al. [13] in patients presenting a monogenic form of diabetes, Maturity Onset Diabetes of the Young type 3, termed MODY3. This form of familial diabetes with autosomal dominant transmission is characterised by the onset of noninsulin-dependent diabetes in children and young adults. During our study of HA, inactivation of the two alleles of the HNF1a gene was observed in either patients presenting with MODY3, with a mutation of constitutional origin and inactivation of the second allele in the tumour, or in 90% of cases in a sporadic manner, the two mutations being somatic (OMIM#142330). Furthermore, we identified two-allele mutations of HNF1a in two cases in a screened series of Journal of Hepatology 40 (2004) 1036–1039 www.elsevier.com/locate/jhep