RB1 and cancer: Altogether, our data suggest that the E7 oncoprotein of oncogenic HPVs interferes with the pRB–E2F axis in cancer cells and evokes a conserved germ cell–like program in HPV-driven tumors, which, even when reduced to the top two genes (CDKN2A and SYCP2), accurately distinguishes HPV-driven from mutation-driven tumors and outperforms established clinical markers (Fig. 3H).