Remarkably, loss-of-function mutations in TSC1 or TSC2 (~10%), and gain-of-function mutations in MTOR (~6%) are common in ccRCC and correlated with rapalog response in therapeutic outlier studies; and Tsc1 and Tsc2 expression levels are down-regulated in Vhl-/-;Pbrm1-/- mouse ccRCC tumors [17, 22, 42, 61–63]. Here, TSC2 is linked to nonpapillary renal cell carcinoma.