VHL and cancer: Besides the most important gatekeeper gene (TP53), from the current COSMIC we detected cancer-specific frequently mutated genes that have been widely known to play critical role in tumor progression, e.g., the APC and PI3KCA genes in large intestine cancer33, the BRAF gene in skin cancer32, the KRAS gene in pancreatic cancer34, the VHL and PBRM1 genes in kidney cancer, and the CTNNB1 and KDM5A genes in liver cancer35, 36.