Frequent inactivating germline mutations in DNA repair genes in patients with Ewing sarcoma Germline mutations in Ewing sarcoma

PURPOSE: Ewing sarcoma is a highly malignant small round blue cell tumor that predominantly affects the adolescent and young adult population. It has long been suspected that a genetic predisposition exists for this cancer, but the germline genetic underpinnings of this disease have not been well established. METHODS: We performed germline variant analysis of whole genome or whole exome sequencing of samples from 175 patients affected by Ewing sarcoma. RESULTS: We discovered pathogenic or likely pathogenic germline mutations in 13.1% of our cohort. Pathogenic mutations were highly enriched for genes involved with DNA damage repair and for genes associated with cancer predisposition syndromes. CONCLUSION: Our findings reported here have important clinical implications for patients and families affected by Ewing sarcoma. Genetic counseling should be considered for patients and families affected by this disease to take advantage of existing risk management strategies. Our study also highlights the importance of germline sequencing for patients enrolled on precision medicine protocols.