Discovering the Timing and Origins of Bone and Soft Tissue Cancers

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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