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Sci Rep. 2020 Jan 27;10(1):1224. doi: 10.1038/s41598-020-58179-0.

Depicting the genetic architecture of pediatric cancers through an integrative gene network approach.

Author information

1
Univ Rennes, CNRS, IGDR (Institut de génétique et développement de Rennes) - UMR 6290, Rennes, France.
2
Somatic Cancer Genetics Department, Pontchaillou University Hospital, Rennes, France.
3
Pediatric Oncology Department, Pontchaillou University Hospital, Rennes, France.
4
Pediatric Immuno-Hemato-Oncology Unit, Angers University Hospital, Angers, France.
5
Molecular Genetics and Genomics Department, Pontchaillou University Hospital, Rennes, France.
6
Chemistry Oncogenesis Stress Signaling (COSS) Laboratory - INSERM U1242, Centre de Lutte Contre le Cancer (CLCC) Eugène Marquis, Rennes, France.
7
University Côte d'Azur, IRCAN (Institute for Research on Cancer and Aging of Nice) - CNRS UMR 7284 and INSERM U1081, Centre Antoine Lacassagne, Nice, France.
8
Biomedical Department, Centre Scientifique de Monaco, Monaco, Principality of Monaco.
9
Programme Cartes d'Identité des Tumeurs (CIT), Ligue Nationale Contre le Cancer, Paris, France.
10
Univ Rennes, CNRS, IGDR (Institut de génétique et développement de Rennes) - UMR 6290, Rennes, France. marie.detayrac@univ-rennes1.fr.
11
Molecular Genetics and Genomics Department, Pontchaillou University Hospital, Rennes, France. marie.detayrac@univ-rennes1.fr.

Abstract

The genetic etiology of childhood cancers still remains largely unknown. It is therefore essential to develop novel strategies to unravel the spectrum of pediatric cancer genes. Statistical network modeling techniques have emerged as powerful methodologies for enabling the inference of gene-disease relationship and have been performed on adult but not pediatric cancers. We performed a deep multi-layer understanding of pan-cancer transcriptome data selected from the Treehouse Childhood Cancer Initiative through a co-expression network analysis. We identified six modules strongly associated with pediatric tumor histotypes that were functionally linked to developmental processes. Topological analyses highlighted that pediatric cancer predisposition genes and potential therapeutic targets were central regulators of cancer-histotype specific modules. A module was related to multiple pediatric malignancies with functions involved in DNA repair and cell cycle regulation. This canonical oncogenic module gathered most of the childhood cancer predisposition genes and clinically actionable genes. In pediatric acute leukemias, the driver genes were co-expressed in a module related to epigenetic and post-transcriptional processes, suggesting a critical role of these pathways in the progression of hematologic malignancies. This integrative pan-cancer study provides a thorough characterization of pediatric tumor-associated modules and paves the way for investigating novel candidate genes involved in childhood tumorigenesis.

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