SMAD4 and neoplasm: Unfortunately, the vast majority of tumour suppressor genes are embryonic lethal (for example, Rb1, Pten, Apc, Nf1, Nf2, Ptc, Vhl, Smad4, Atr, Smarca4, Arid1a, Snf5, Nkx2-1, Nkx3-1, Tsc1, Tsc2 and so on), thus leaving very few tumour suppressor genes with which to use this system (for example, p53, Cdkn2a and Atm).