A potential explanation for the difference in pancreatic phenotypes between VHL patients and Pdx1-Cre;HIF2dPA mice is that HIFα activation (by VHL inactivation) occurs locally in VHL patients (second hit hypothesis of hereditary cancer) while broad HIFα activation in the pancreas is achieved in Pdx1-Cre;HIF2dPA mice. Here, VHL is linked to hereditary cancer.