The mechanisms of somatic genome rearrangements in pediatric brain tumors

摘要 儿童脑癌仍然是一种致命的疾病。这些肿瘤的驱动因素在很大程度上仍不清楚。这个 与成人肿瘤相比，肿瘤携带的体细胞点突变要少得多。相比之下，它们拥有大量的 体细胞基因组重排，如缺失、倒位和易位。一般来说，遗传的 改变是由自发突变、外部诱变剂、错误的DNA复制和异常引起的 DNA损伤修复。然而，是什么导致了儿童脑瘤的基因组重排？ 重新安排在多大程度上有助于疾病进展和治疗反应尚不清楚。一个 更好地了解突变机制不仅对于解决疾病的原因是必要的，而且 还可以指导临床实践和药物开发。例如，如果一些基因组重排是 与诱变剂相关的是，避免诱变剂可以帮助降低癌症风险。如果某些生殖系变种 与躯体重排的发生增加有关，携带这种变异的个体 在较早的年龄接受癌症筛查。此外，DNA损伤修复基因和途径的变化 可能被用作预后生物标记物，一些途径甚至可能成为药物的靶点。作为该计划的一部分 加布里埃拉·米勒儿童优先计划，儿童脑瘤组织联合会(CBTTC)收集了一份 并对800个肿瘤基因组和转录本进行了测序，其中 为我们提供了一个对体细胞基因组进行全面研究的前所未有的机会 重新安排。我们的研究旨在通过数学方法剖析体细胞基因组重排的原因 使用基因组测序数据对突变机制进行建模。我们希望找出各种因素 负责形成儿童脑肿瘤的体细胞基因组重排，并提供新的 对疾病预防和治疗的见解。

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.