Collectively, our discoveries made in an aggressive childhood cancer exemplify how oncogenic cooperation between a cancer driver-mutation (here EWSR1-FLI1) and a regulatory germline variant (here a polymorphic enhancer-like GGAA microsatellite) can create a major source of inter-tumor heterogeneity determining clinical outcome and drug response through modulation of a druggable key downstream player (Fig. 4d). Here, FLI1 is linked to childhood malignant neoplasm.