REN and neoplasm: 58) harbour mutations in PTCH1. Tumours with ligand-independent activation of HH pathway carry genetic aberrations that confer cell-intrinsic growth properties to the tumour. The most frequent alterations found are inactivating mutations of pathway repressors, such as PTCH1 (Refs 59, 60), SUFU (Refs 61, 62) or REN (Ref. 63), mutations leading to constitutive activation of SMO (Ref. 64), or gene amplifications of GLI1 and GLI2 (Refs 65, 66), that result in constitutive HH pathway activation.