Discovering the Timing and Origins of Bone and Soft Tissue Cancers - 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
