We postulate that the contrast between RCC and non-RCC cancer types reflects the contrast between highly un-physiological HIF activation following inactivation of VHL in most RCC, and more physiological activation of HIF by micro-environmental hypoxia in other cancers (i.e. in this setting it is un-physiological dysregulated activation, which creates the selective pressure for modulation). The gene discussed is VHL; the disease is renal cell carcinoma.