EPAS1 and polycythemia: Germline mutations in HIF-2α have also been reported to be associated with PCC/PGL development; nonetheless, as certain germline mutations in HIF-2α only lead to polycythemias and not tumors (115, 116), it is thought that such gain-of-function mutations alone are not sufficient for tumorigenesis, and that, presumably, simultaneous loss-of-function or somatic mutations in other genes may also be necessary (115–117).