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

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 genedisease 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.Cancer remains the leading cause of death by disease in children of less than fourteen years of age 1 . Improving the management of pediatric cancer is essential and will benefit from more accurate diagnosis, new personalized treatment and development of specific and less damaging therapies. To face these challenges, it is necessary to unravel the complete genetic repertoire of pediatric malignancies. Recent studies have improved the understanding of the genetics of childhood cancer, but have mainly focused on depicting the germline and somatic mutational landscape of these diseases [2][3][4] .Several evidences demonstrated that the biology and genetics of pediatric cancers set them apart from adult tumors 4,5 . Childhood cancers have a 14-times lower mutation rate compared to adult tumors and mostly arise from mutations in few driver genes. Somatic alterations mostly target a handful of major genes such as CDKN2A, NOTCH1, NRAS, KRAS or TP53, and pathways disrupted by driver alterations are either common to cancer (e.g. cell cycle) or specific to pediatric cancer histotypes 4 . More than half of the driver genes are restricted to one cancer histotype and 83% of them are not shared between hematologic and solid tumors. This indicates that certain genes and pathways are exclusively dysregulated in a single type of childhood cancer. reconstructed 100 times with the same parameters on a random selection of the initial samples. The robustness was measured as the number of times a gene was assigned to the observed m...

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