Molecular Mechanisms Underlying Soft Tissue Sarcoma Predisposition

In developed countries, the 2 largest contributors to premature mortality are behavior (40%) and genetics (35%), in contrast to access, which accounts for 10%, although we suspect that the former two may impact the latter. Patients at genetic risk of cancer are an important subset for several clinically relevant reasons. Importantly, appropriate testing for many of these high-penetrance genes leading to cancer predisposition have clear clinical validity, clinical utility and actionability. The long-term goal of this project is to elucidate hereditary genetic defects leading to soft tissue sarcomas (STS) to develop better therapies for our patients, and generate knowledge that could be applicable to other conditions. Using next-generation sequencing of patients with familial, multiple and/or rare cancers, our group has successfully characterized the frequency of germline mutations in known tumor predisposition genes in different cancer subtypes. In a pilot study, we recently identified that a significant proportion (22%) of patients with apparently sporadic STS harbor pathogenic germline mutations in known cancer predisposition genes, suggesting that a subset of STS may have a previously not recognized underlying genetic predisposition. We have also identified novel cancer predisposition genes such as the CDNK2A and DNA damage repair (DDR) pathway genes, through studying families with a strong history of sarcomas. In the next three years, we would like to continue the identification of new genetic defects in STS using both clinical and biochemical phenotyping alongside next generation sequencing and related technologies, in addition to classic genetic approaches; elucidate further the role CDNK2A and the DDR pathway plays in soft tissue sarcoma tumorigenesis and utilize cells engineered to be sensitive to CDNK2A and DDR pathway defects for in-vitro drug screening. This approach is expected to lead to the discovery of molecules that may be used therapeutically for STS.