Furthermore, the list of typically early drivers includes most other highly recurrent CpG-dependent cancer driver genes identified in the present work, such as TP53, PIK3CA, CDKN2A, PTEN, APC, RB1, FBXW7, NFE2L2, IDH1, PIK3R128, consistent with the notion that hypermutability of CpG of these cancer genes plays a critical role in the initiation of carcinogenesis. The gene discussed is RB1; the disease is cancer.