Role of liver and hematopoietic somatic mosaicism in the progression of chronic liver diseases to cirrhosis
Description: Background: Somatic mosaicism is observed in most non-tumor tissues including liver mosaicism and clonal hematopoiesis of indeterminate significance (CHIP) in humans. We would like to assess the role of liver and hematopoietic somatic mosaicism in the progression of chronic liver disease to cirrhosis. Methodology: In 1750 livers samples (300 normal livers, 200 F2-F3, 200 cirrhosis without HCC, 800 livers from patients with HCC (from adults) and 100 fetal livers and 150 livers (from children)), we will search for the mutation S22W of FOXO1 (most recurrent mutations in liver in preliminary data) using digital droplet PCR and correlate with progression to cirrhosis and HCC. We will perform ultradeep WES of the liver (500X) in a series of 150 liver samples in order to identify new somatic mutations involved in liver mosaicism and will validate these results in the whole series of livers. Combining single cell and spatial transcriptomic of 15 livers positive for FOXO1 mutations, we will decipherer the transcriptome of hepatocytes with FOXO1 mutations. To identify CHIP, we will perform leucocytes WES at 200X in 400 adult patients (200 chronic liver disease F2/F3, 200 cirrhosis without HCC) and compare with healthy population of the UK biobank. We will correlate CHIP with liver somatic mosaicism, with the constitutional variants predisposing to chronic liver diseases (PNPLA3, TM6SF2, WNT3A/WNT9A etc….) and with progression to cirrhosis. Finally, we will assess the impact of somatic mutation S22W FOXO1 in mouse models of metabolic steatotic liver disease in order to assess the functional consequence of somatic mosaicism in fibrosis and HCC development. Expected results: we aim to decipher the role of liver somatic mosaicism and CHIP in chronic liver disease and identify new biomarkers to stratify the management of these patients. We will like also to characterize the functional consequences of liver somatic mosaicism in the liver.
Funder: Agence Nationale de la Recherche
Amount: €680,500
Funding type: research
Funder scheme: AAPG2025
Start date: 2025-11-01
Investigator: Jessica ZUCMAN-ROSSI
Institution: SORBONNE UNIVERSITÉ
Funded outputs count: 1
Funder award ID: ANR-25-CE17-4347
OpenAlex ID: G6370734929