Xue et al. used mice with an intestine-specific Vhl disruption (VhlΔIE)) crossed with CRC-predisposed mice (Apcmin/+) to reveal that the activation of HIF-2α in VhlΔIE/Apcmin/+ mice led to a dramatic increase in colon tumor multiplicity and incidence, with most tumors evolving into carcinomas, while Apcmin/+ mice typically develop mainly small intestinal tumors. This evidence concerns the gene EPAS1 and colonic neoplasm.