Nonetheless, the truncal nature of VHL mutation in ccRCC evolution, and the long latency postulated between biallelic VHL inactivation and PBRM1/BAP1 inactivation (9, 59) suggest that time-accrued effects of VHL inactivation inform the oncogenic trajectory of at least some renal cells. The gene discussed is PBRM1; the disease is nonpapillary renal cell carcinoma.