RB1 and cancer: In the context of the MED12-independent pathway, malignant PTs might arise de novo following the early acquisition of genetic alterations affecting cancer genes, including not only TERT genetic alterations, but, most strikingly, activation of oncogenes, such as EGFR, and/ or loss of function of tumor suppressor genes, such as RB1 and TP53 (Fig. 4).