Discovering the Timing and Origins of Bone and Soft Tissue Cancers

总结 肉瘤是骨和结缔组织的癌症，影响儿童的比例高于成人。 许多儿童肉瘤很难诊断，这可能导致治疗延误。在复发时，童年 肉瘤患者的生存率很低，40年来几乎没有改善。我们假设童年 肉瘤的真正开始-它们的癌前突变或起源细胞-实际上发生在癌症发生之前的许多年。 诊断.在Gabriella米勒儿童优先、CCDI和R 03提案的支持下，我们将确定 时间顺序和分子过程导致儿童肉瘤。为此，我们借鉴了 样本和临床数据来自我们的存储库，包含超过6，000个样本。高质量的标本已被 选择以告知肉瘤发展中的每个关键时间标志-从肿瘤开始， 关键致癌融合和恶性潜能的产生，可能的复发或转移。这 该项目将利用现有的生物信息学管道，在两个平行的目标下进行。首先，我们将找到 儿童软组织和骨癌的起源突变。我们发现童年 尤文肉瘤和骨肉瘤在诊断前数年就开始了，有时在子宫内就开始了.我们将 重建罕见肉瘤的系统发育树我们会看到早发性肿瘤 与早期肿瘤发生有关。其次，我们将使用骨和软组织的非肿瘤性肿瘤作为 肉瘤起始模型，无增殖。作为补充，我们将对晚出现的 儿童肉瘤-从成人谁开发肉瘤类型通常只在儿童中发现。我们将学习 成人和儿童肉瘤是否由相同的致突变过程引起。我们将 确定基因融合的形成特征，这是早期肉瘤形成的主要驱动因素。最后， 我们将使用同样的方法来检查复发的肉瘤患者， 常规短读方法错过的突变。总的来说，这些数据将提供一个全面的 了解儿童肉瘤的恶性进展。这将为早期的试验奠定基础。 儿童肉瘤的治疗干预，例如通过预测复发的演变轨迹 在它发生之前。 1

SUMMARY Sarcomas are cancers of the bone and connective tissue that affect a higher proportion of children than adults. Many childhood sarcomas are difficult to diagnose, which can lead to therapeutic delays. At relapse, childhood sarcoma patients have poor survival, with little improvement seen in 40 years. We hypothesize that childhood sarcomas’ true beginnings – their pre-malignant mutations or cells of origin – in fact occur many years prior to diagnosis. With support from the Gabriella Miller Kids First, CCDI, and this R03 proposal, we will determine the temporal order and molecular processes that give rise to childhood sarcomas. To do so, we have drawn on samples and clinical data from our repositories containing >6,000 samples. High quality specimens have been selected to inform each of the key temporal landmarks in the development of sarcoma – from tumor initiation, to the generation of critical oncogenic fusions and malignant potential, to possible relapse or metastasis. This project will be pursued in two parallel aims, using existing bioinformatics pipelines. First, we will find the originating mutations for childhood soft tissue and bone cancers. This is motivated by our finding that childhood Ewing- and osteo- sarcomas are initiated multiple years before diagnosis, sometimes starting in utero. We will reconstruct phylogenetic trees for rare sarcomas in this cohort. We will see how often early-onset tumors are associated with early oncogenesis. Second, we will use non-neoplastic tumors of bone and soft tissue as a model for sarcoma initiation, without proliferation. Complementing this, we will have sequenced late-emerging childhood sarcomas - from adults who developed sarcoma types typically found only in children. We will learn whether adult and childhood sarcomas of the same type are driven by the same mutagenic processes. We will determine the formation signatures of gene fusions, which are major drivers of early sarcomagenesis. Finally, we will use the same approach to examine sarcoma patients at relapse, to find clinically useful secondary mutations missed by conventional short read approaches. Collectively, these data will provide a thorough understanding of malignant progression in childhood sarcoma. This will lay the foundation for trials of early therapeutic intervention in childhood sarcoma, for example by predicting the evolutionary trajectory of relapse before it occurs. 1