To perform functional studies on candidate rare tumor drivers (Figure 1C), specific siRNAs targeting the four genes were employed to transfect human osteosarcoma cells (U2OS) and human lung cancer cells (A549) (Figure S1A, Supporting Information), which revealed that only SETD8 knockdown retarded cell proliferation and induced increases in apoptosis (Figure S1B–E, Supporting Information). Here, KMT5A is linked to lung carcinoma.