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

Clara Savary (1) , Artem Kim (1) , Alexandra Lespagnol (2) , Virginie Gandemer (1, 2) , Isabelle Pellier (3) , Charlotte Andrieu (2, 4) , Gilles Pagès (5, 6) , Marie-Dominique Galibert (1, 2) , Yuna Blum (7) , Marie de Tayrac (1, 2)

1 IGDR - Institut de Génétique et Développement de Rennes
2 Centre Hospitalier Universitaire de Rennes [CHU Rennes] = Rennes University Hospital [Ponchaillou]
3 CHU Angers - Centre Hospitalier Universitaire d'Angers
4 COSS - Chemistry, Oncogenesis, Stress and Signaling
5 IRCAN - Institut de Recherche sur le Cancer et le Vieillissement
6 CSM - Centre Scientifique de Monaco
7 CIT - (le programme) Cartes d'identité des tumeurs

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.

Domaines: Cancer

Clara Savary, Artem Kim, Alexandra Lespagnol, Virginie Gandemer, Isabelle Pellier, et al.. Depicting the genetic architecture of pediatric cancers through an integrative gene network approach. Scientific Reports, 2020, 10 (1), pp.1224. ⟨10.1038/s41598-020-58179-0⟩. ⟨hal-02472258⟩