Genomic evolution of high-risk soft tissue sarcomas under thermo- and chemotherapeutic selection pressure

The integration of regional hyperthermia into the multimodal treatment of patients with localized high-risk soft tissue sarcomas has been shown to improve overall survival. However, specific effects on the tumors’ genetic makeup and biology are largely unknown. Since clonal selection of malignant cells capable of thermoresistance might contribute to disease progression, a better understanding of the induced tumor evolution could inform strategies for improving treatment efficacy. We performed whole exome sequencing on paired sarcoma samples obtained before and after treatment with chemotherapy combined with regional hyperthermia (<i>n</i> = 12 patients; <i>n</i> = 9 paired samples, <i>n</i> = 3 post-treatment only). Tumor evolution was evident in all paired samples, with shifts in small- and large-scale genomic alterations. Overall, these alterations appeared tumor-specific, but recurrent mutations in histone H3-modifying genes were found exclusively in post-therapeutic samples. Our findings showcase the diversity of genomic evolution patterns in sarcomas emerging under combined thermo- and chemotherapeutic selection pressure, indicating that treatment response may vary according to the specific tumor composition. With previous studies linking histone functions to heat stress response, the alterations found in genes modifying H3 in our post-therapeutic cohort provide biological evidence for synergy of chemotherapy combined with regional hyperthermia in soft tissue sarcomas.