Profiling of somatic mutation in high- and low-risk sarcoma

Soft tissue sarcoma (STS) are rare mesenchymal tumors with heterogeneous clinical course. Myxofibrosarcomas are among the most common STS, presenting in the extremities of older adults. These tumors are mostly treated surgically due to their poor response to radiation or systemic treatments. Because of their highly infiltrative nature, myxofibrosarcomas have the highest rate of amputation among the soft tissue sarcomas, which negatively affects patients’ quality of life. Even patients with lower grade tumors have to be closely monitored because the tumors may recur locally, multiple times, often increasing in grade at relapse. On the other end of the spectrum, high grade myxofibrosarcomas metastasize in 30 to 40% of the cases and these lesions rarely respond to chemotherapy. There are currently no molecular or clinical biomarkers to reliably predict which tumors will locally relapse or metastasize, leaving many patients overtreated with invalidating amputations, or undertreated without systemic therapy until metastases are already established and harder to manage. Consequently, survival rate in this patient population has not changed in the last 20 years (68-70% at five years). Myxofibrosarcomas are genetically complex tumors, where no recurrent actionable mutations have been discovered. However, recent molecular profiling studies of larger cohorts of tumors have shown that myxofibrosarcoma comprises three different methylation subgroups, with different clinical outcome, immune infiltration and mutational profile. Molecular profiling integrated with clinical or histological biomarkers has improved patient stratification in several human conditions. However, this has not been attempted in this type of sarcomas. Our MoH cohort represent a unique opportunity to investigate this rare cancer type at very high resolution. Only one study has previously attempted whole genome sequencing of this tumor type and only analyzed five samples. Due to the paucity of amenable tissue in large biobanks, whole genome sequencing of this tumor type has been lagging behind more common cancers.  With support from MoH we collected will sequence thirty cases: the largest cohort for this tumor type. Importantly, clinical annotation of our cohort will allow us to correlate molecular features and clinical outcome and potentially develop novel biomarkers to separate the high-risk vs low risk patients.