Integrated Genomic Analysis Identifies Driver Genes and Cisplatin-Resistant Progenitor Phenotype in Pediatric Liver Cancer

被引：51

作者：

Hirsch, Theo Z. ^{[1
]}

Pilet, Jill ^{[1
]}

Morcrette, Guillaume ^{[1
,2
]}

Roehrig, Amelie ^{[1
]}

Monteiro, Benedict J. E. ^{[1
]}

Molina, Laura ^{[1
,3
]}

Bayard, Quentin ^{[1
]}

Trepo, Eric ^{[1
,4
]}

Meunier, Lea ^{[1
]}

Caruso, Stefano ^{[1
]}

Renault, Victor ^{[5
]}

Deleuze, Jean-Francois ^{[5
,6
]}

Fresneau, Brice ^{[7
]}

Chardot, Christophe ^{[8
]}

Gonzales, Emmanuel ^{[9
,10
]}

Jacquemin, Emmanuel ^{[9
,10
]}

Guerin, Florent ^{[11
]}

Fabre, Monique ^{[12
]}

Aerts, Isabelle ^{[13
]}

Taque, Sophie ^{[14
]}

Laithier, Veronique ^{[15
]}

Branchereau, Sophie ^{[11
]}

Guettier, Catherine ^{[16
]}

Brugieres, Laurence ^{[7
]}

Rebouissou, Sandra ^{[1
]}

Letouze, Eric ^{[1
]}

Zucman-Rossi, Jessica ^{[1
,17
]}

机构：

[1] Univ Paris, Sorbonne Univ, Ctr Rech Cordeliers, INSERM, 15 Rue Ecole Med, F-75006 Paris, France

[2] Robert Debre Hosp, AP HP, Dept Pediat Pathol, Paris, France

[3] Univ Pittsburgh, Sch Med, Dept Pathol, Pittsburgh, PA USA

[4] Univ Libre Bruxelles, CUB Hop Erasme, Dept Gastroenterol Hepatopancreatol & Digest Onco, Brussels, Belgium

[5] Fdn Jean Dausset CEPH, Lab Bioinformat, Paris, France

[6] Univ Paris Saclay, Commissariat Energie Atom & Energies Alternat, Ctr Natl Rech Genom Humaine, Evry, France

[7] Univ Paris Saclay, Gustave Roussy, Dept Children & Adolescents Oncol, Villejuif, France

[8] Univ Paris, Necker Hosp, AP HP, Paris, France

[9] Univ Paris Saclay, Bicetre Univ Hosp, AP HP,FILFOIE,ERN RARE LIVER, Pediat Hepatol & Liver Transplantat Unit,Natl Ref, Le Kremlin Bicetre, France

[10] Univ Paris Saclay, Hepatinov, INSERM UMR S 1193, Orsay, France

[11] Paris Saclay Univ, Bicetre Hosp, AP HP, Dept Pediat Surg, Orsay, France

[12] Univ Paris 05, Hop Univ Necker Enfants Malad, AP HP, Dept Pathol,Ctr Univ Paris, Paris, France

[13] PSL Res Univ, Oncol Ctr SIREDO, Inst Curie, Paris, France

[14] CHU Fontenoy, Dept Pediatrie, Rennes, France

[15] Ctr Hosp Univ Besancon, Dept Children Oncol, Besancon, France

[16] Paris Saclay Univ, Hop Bicetre, AP HP, Dept Pathol,INSERM U1193, Orsay, France

[17] Hop Europeen Georges Pompidou, AP HP, Paris, France

来源：

CANCER DISCOVERY | 2021年 / 11卷 / 10期

关键词：

HEPATOCELLULAR CARCINOMAS; MUTATIONAL SIGNATURES; HEPATOBLASTOMA; LANDSCAPE; NEUROBLASTOMA; HETEROGENEITY; MECHANISMS; DISCOVERY; FRAMEWORK; REVEALS;

D O I：

10.1158/2159-8290.CD-20-1809

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

Pediatric liver cancers (PLC) 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 patients with hepatoblastoma, all before three 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. SIGNIFICANCE: PLCs are deadly when they resist chemotherapy, with limited alternative treatment options. Using a multiomics approach, we identified PLC driver genes and the cellular phenotype at the origin of cisplatin resistance. We validated new treatments targeting these molecular features in cell lines and xenografts.

引用

页码：2524 / 2543

页数：20

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