Analysing pathways of carcinogenesis in benign and malignant human hepatic tumours Print E-mail
a- Studying pathways of carcinogenesis in hepatocellular adenomas and hepatic tumours that have developed on healthy liver
ImageIn terms of hepatocellular adenomas and the rare cases of HCC mutated for HNF1, the group is continuing to studying the function of HNF1 in hepatocyte proliferation by analysing the transcriptome of a series of adenomas with biallelic inactivation of the gene, compared to that of normal hepatic tissue. The aim of this project is to identify the genes that are deregulated by hepatocyte biallelic inactivation of HNF1 and that are involved in cell proliferation.

b- Studying the pathways of carcinogenesis that are altered in HCCs
As far as HCCs are concerned, we initially analysed over 500 markers of “structural” genetic alterations (mutations in P53, ß-catenine and Axine 1; HNF1 LOH on the entire genome) in over 200 HCCs. We thus identified a mechanism of hepatic carcinogenesis that is associated with chromosomal instability in half of the HCCs (Laurent-Puig, Gastroenterology, 2001). This approach will be continued by studying the transcriptome on a subset of 70 of these tumours, using the Affymetrix technique and as part of the CIT2 project. The aim of this project will be to identify:
• The pathways of carcinogenesis specific for aetiological factors,
• Alterations in secondary expression, depending on the pathways of the structural genetic alterations already characterised (the TP53 and Wnt pathways in particular),
• New altered pathways of carcinogenesis, by comparing expression profiles of tumours with chromosomal alterations and defining minimal common deleted regions in the tumours.
 
Genotype - phenotype correlation in hepatocellular tumours Print E-mail
ImageRegarding benign liver tumours, we aim to identify the relationships between HNF1 mutations and the phenotype of the tumour. In order to carry out the study on “genotype-phenotype” associations successfully in hepatocellular tumours that have developed in healthy liver, we have formed a network that includes 13 hospital teams in France supported by the Inserm.
Its aim is the prospective analysis and validation of 300 tumours developed on healthy liver.
In this series of tumours, we will determine the spectrum of HNF1 mutations and the known pathways of carcinogenesis, such as Wnt activation. This large series of tumours will make it possible to look for diagnostic and prognostic markers for hepatocellular tumours that develop on healthy liver.

Regarding HCCs, using concomitant analysis of a large number of genetic alterations and anatomical/clinical parameters, we have been able to identify close relationships between the clinical characteristics (in particular infection with hepatitis B virus, tumour differentiation, and patient survival) and somatic genetic alterations. We will continue the study of these genotypic/phenotypic associations with the results concerning the transcriptome of the same tumours, with the aim of identifying new factors related to tumour differentiation and prognosis.
 
 


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