Collectively our data lead to the hypothesis that renal tumorigenesis in BHD patients could follow two different paths: either pro-inflammatory effects of specific E-box and/or ISRE genes are further aggravated by secondary mutations during tumor evolution, or growth-suppression by IFN signature genes, which is dominant over the effects of TFE3 activation, is gradually lost by additionally acquired mutations thus leading to TFE3-driven tumor progression. The gene discussed is TFE3; the disease is neoplasm.