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Integrated genomic analysis identifies driver genes and cisplatinresistant progenitor phenotype in pediatric liver cancer

Abstract : Pediatric liver cancers (PLCs) comprise diverse diseases affecting infants, children and adolescents. Despite overall good prognosis, PLCs display heterogeneous response to chemotherapy. Integrated genomic analysis of 126 pediatric liver tumors showed a continuum of driver mechanisms associated with patient age, including new targetable oncogenes. In 10% of hepatoblastoma patients, all before 3 years old, we identified a mosaic premalignant clonal expansion of cells altered at the 11p15.5 locus. Analysis of spatial and longitudinal heterogeneity revealed an important plasticity between 'Hepatocytic', 'Liver Progenitor' and 'Mesenchymal' molecular subgroups of hepatoblastoma. We showed that during chemotherapy, 'Liver Progenitor' cells accumulated massive loads of cisplatin-induced mutations with a specific mutational signature, leading to the development of heavily mutated relapses and metastases. Drug screening in PLC cell lines identified promising targets for cisplatin-resistant progenitor cells, validated in mouse xenograft experiments. These data provide new insights into cisplatin resistance mechanisms in PLC and suggest alternative therapies.
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https://www.hal.inserm.fr/inserm-03212814
Contributor : Jessica Zucman-Rossi <>
Submitted on : Friday, April 30, 2021 - 6:59:25 AM
Last modification on : Wednesday, June 2, 2021 - 4:26:43 PM
Long-term archiving on: : Saturday, July 31, 2021 - 6:11:17 PM

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Theo Hirsch, Jill Pilet, Guillaume Morcrette, Amelie Roehrig, Benedict Monteiro, et al.. Integrated genomic analysis identifies driver genes and cisplatinresistant progenitor phenotype in pediatric liver cancer. Cancer Discovery, American Association for Cancer Research, 2021, pp.candisc.1809.2020. ⟨10.1158/2159-8290.CD-20-1809⟩. ⟨inserm-03212814⟩

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