Soft tissue sarcomas of adults: state of the translational science.

TLDR

Sarcomas, though rare, are biologically significant mesodermal malignancies whose mutations and translocations reveal aberrant signaling pathways and therapeutic targets, including EWS gene family fusions found in five sarcoma subtypes. The study aims to accelerate sarcoma progress by leveraging genomics and proteomics technologies and ensuring accurate histopathological diagnosis with validated reagents and consistent methodologies on adequate tissue samples. Multicenter coordinated trials, exemplified by imatinib mesylate studies in metastatic gastrointestinal stromal tumors, provide the framework for rapid morbidity and mortality reduction. Targeted inhibition of c‑kit in gastrointestinal stromal tumors is clinically effective, while molecular and chromosomal profiling clarifies histopathology and, together with improved imaging and treatment protocols, enhances local control.

Abstract

Sarcomas--like leukemias, which are also mesodermal malignancies--carry biological significance disproportionate to their clinical frequency. Identification of mutations and translocations associated with these tumors has illuminated aberrant signaling pathways that cause these diseases, determine their behavior, and are therapeutic targets. Activated receptor-associated tyrosine kinase c-kit, mutated in most gastrointestinal stromal tumors, has proven a clinically effective target for enzyme inhibition. A translocation involving a single gene family, consisting of EWS and related genes, has been identified in five different sarcomas, and its chimeric protein products could prove similarly amenable to inhibitors. Resolution of the histopathological complexity is being aided by data from molecular and chromosomal characterization. Improvements in imaging, definition of prognostic factors, and surgical and radiotherapeutic treatment have resulted in improved local control. Continued progress will depend on further adapting the rapidly evolving technologies of genomics and proteomics. It will also depend upon accurate histopathological diagnosis based on validated reagents and consistent methodologies applied to adequate tissue samples derived from patients with complete clinical data. Finally, multicenter, coordinated trials, such as those that occurred with assessment of imatinib mesylate in metastatic gastrointestinal stromal tumors, will assure the most rapid reductions in morbidity and mortality.