[Integrative molecular pathology of cancer].

The field of molecular pathology has revolutionized our understanding of relevant oncogenic alterations in cancer and yielded new diagnostic tools and therapeutic approaches for personalized oncology, especially for malignancies of adulthood. However, many pediatric tumors, such as Ewing sarcoma, are characterized by a remarkable paucity of recurrent driver mutations, which are usually not suitable as drug targets. Despite the relative homogeneity of the somatic mutational profiles, these tumors nevertheless exhibit a relatively strong clinical heterogeneity, indicating additional modulating factors. In this regard, a recent study could demonstrate that the mode of action of the EWSR1-FLI1 (Ewing sarcoma breakpoint region 1-Friend leukema integration 1) fusion oncoprotein, which is pathognomonic for Ewing sarcoma, is influenced by inherited genetic variants in regulatory DNA elements, which may ultimately affect the course of the disease and also enable new therapeutic options. Thus, these investigations demonstrate in the Ewing sarcoma model that the function of a driver mutation needs to be interpreted in its germline context, which should be taken into account in an integrative approach by the molecular pathology of the future.