Integrated genomic analysis identifies driver genes and cisplatin-resistant progenitor phenotype in pediatric liver cancer

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.

Type: Other
Archiver: European Genome-Phenome Archive (EGA)

1 Dataset 4 Publications

Click on a Dataset ID in the table below to learn more, and to find out who to contact about access to these data

Dataset ID	Description	Technology	Samples
EGAD00001007858	None	HiSeq X Five Illumina HiSeq 4000 Illumina NovaSeq 6000	234

Publications	Citations
Integrated Genomic Analysis Identifies Driver Genes and Cisplatin-Resistant Progenitor Phenotype in Pediatric Liver Cancer. Hirsch TZ, Pilet J, Morcrette G, Roehrig A, Monteiro BJE, Molina L, Bayard Q, Trépo E, Meunier L, Caruso S, Renault V, Deleuze JF, Fresneau B, Chardot C, Gonzales E, Jacquemin E, Guerin F, Fabre M, Aerts I, Taque S, Laithier V, Branchereau S, Guettier C, Brugières L, Rebouissou S, Letouzé E, Zucman-Rossi J. Cancer Discov 11: 2021 2524-2543	27
Preneoplastic liver colonization by 11p15.5 altered mosaic cells in young children with hepatoblastoma. Pilet J, Hirsch TZ, Gupta B, Roehrig A, Morcrette G, Pire A, Letouzé E, Fresneau B, Taque S, Brugières L, Branchereau S, Chardot C, Aerts I, Sarnacki S, Fabre M, Guettier C, Rebouissou S, Zucman-Rossi J. Nat Commun 14: 2023 7122	1
Single-cell multiomics reveals the interplay of clonal evolution and cellular plasticity in hepatoblastoma. Roehrig A, Hirsch TZ, Pire A, Morcrette G, Gupta B, Marcaillou C, Imbeaud S, Chardot C, Gonzales E, Jacquemin E, Sekiguchi M, Takita J, Nagae G, Hiyama E, Guérin F, Fabre M, Aerts I, Taque S, Laithier V, Branchereau S, Guettier C, Brugières L, Fresneau B, Zucman-Rossi J, Letouzé E. Nat Commun 15: 2024 3031	5
Divergent WNT signaling and drug sensitivity profiles within hepatoblastoma tumors and organoids. Kluiver TA, Lu Y, Schubert SA, Kraaier LJ, Ringnalda F, Lijnzaad P, DeMartino J, Megchelenbrink WL, Amo-Addae V, Eising S, de Faria FW, Münter D, van de Wetering M, Kerl K, Duiker E, van den Heuvel MC, de Meijer VE, de Kleine RH, Molenaar JJ, Margaritis T, Stunnenberg HG, de Krijger RR, Zsiros J, Clevers H, Peng WC. Nat Commun 15: 2024 8576	1