The mechanisms of somatic genome rearrangements in pediatric brain tumors

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ABSTRACT Pediatric brain cancer remains a deadly disease. What drives these tumors are still largely unknown. The tumors carry a lot fewer somatic point mutations than adult tumors. In contrast, they harbor a large number of somatic genome rearrangements, such as deletions, inversions and translocations. Generally, genetic alterations are caused by spontaneous mutations, external mutagens, erroneous DNA replication and aberrant DNA damage repair. However, what induces genomic rearrangements in pediatric brain tumors and to what extent the rearrangements contribute to disease progression and treatment response remain unknown. A better understanding of mutational mechanisms is not only necessary to resolve the causes of the disease, but can also guide clinical practices and drug development. For example, if some genomic rearrangements are associated with mutagens, avoiding the mutagens can help lower the risk of cancer. If certain germline variants are associated with increased occurrence of somatic rearrangements, individuals carrying such variants shall be screened for cancer at earlier age. Furthermore, alterations in DNA damage repair genes and pathways may be used as prognostic biomarkers and some pathways may even be targeted by drugs. As part of the Gabriella Miller Kids First Program, the Children’s Brain Tumor Tissue Consortium (CBTTC) has collected a large number of pediatric brain tumors and sequenced 800 tumor genomes and transcriptomes, which provides us an unprecedented opportunity to perform a comprehensive study on somatic genome rearrangements. Our study aims to dissect the causes of somatic genome rearrangements by mathematically modeling the mutational mechanisms using the genomic sequencing data. We expect to identify factors responsible for the formation of somatic genome rearrangements in pediatric brain tumors and provide new insights to disease prevention and treatment.