Wild-type VHL, PIK3CA, AKT, mTOR, MET or TP53 genes. Genes for succinate dehydrogenase subunits (SDH-A, -B, -C, -D), encode protein components of mitochondrial complex II, linking the Krebs cycle with the electron transport chain, being involved in most cases of SDHD RCC. Germline mutations of SDH-A, SDH-B (1p36.13), SDH-C (1q23.3), SDH-D(11q23.1), SHDAF2, determining double hit inactivation, leads to dysfunction of mitochondrial complex II, increased oxidative stress, genomic injury and HIF1α stabilization. This evidence concerns the gene SDHD and renal cell carcinoma.