SMAD4 and neoplasm: Additionally, the TGFβ family members are also very commonly mutated or deregulated.10 Deletion, downregulation or inactivating mutations can occur in TGFBR1, TGFBR2 and the SMAD effectors (SMAD2–4).11, 12, 13 Frameshift mutations in TGFBR2 have been predominantly identified in CRC with mismatch repair (MMR) defects.14 In tumours with functional MMR, TGFβ signalling is commonly abolished by loss of SMAD4.11, 15