In a new study, which appears in the online journal Nature Communications, Grunewald's team shows how such genetic interplay determines the course of the disease in individual patients. "The clinical course of the disease is very heterogeneous," says Grunewald, "and this variation cannot be attributed to the acquired somatic driver mutation, since this mutation is common to all patients. We therefore took a closer look at the somatic mutation in the context of the individual genome. The acquired mutation occurs in a variety of genetic backgrounds, and it turns out that inherited variations in regulatory elements have a marked effect on how the driver mutation acts in different individuals.
Dr. Thomas Grunewald studies the genetics and molecular pathology of Ewing sarcoma, a malignant bone cancer that is found primarily in children, adolescents and young adults. Most cases of Ewing sarcoma are associated with a single dominant driver mutation which, however, may not be fully sufficient to trigger tumorigenesis. Grunewald leads a Max-Eder Junior Research Group in Paediatric Sarcoma Biology at LMU's Institute of Pathology. In a paper published in Nature Genetics in 2015, he and his colleagues demonstrated that Ewing sarcoma tumorigenesis is driven by the interplay of an acquired somatic mutation that occurs spontaneously in the tissue concerned and an inherited germline variant that is present in all the patient's cells.
All patients with Ewing sarcoma share the same somatic mutation in the affected tissue, but they differ from one another in terms of the genetic variability they have inherited. The driver mutation results in the fusion of two genes, and leads to the production of a hybrid transcription factor, which binds to, and activates other genes. The new study demonstrates that inherited variation in the regulatory sequences of several of these target genes defines their affinity for the hybrid protein. This factor in turn determines the level of their expression - and the rate of growth of the tumor. This interplay is what accounts for the differences in the severity of the disease from patient to patient. "Up to now, personalized cancer therapy has focused mostly on the acquired somatic mutations.
