SMAD4 and neoplasm: HPV+ tumours also showed frequent loss of function of TRAF3, NSD1, FAT1, NOTCH1, and SMAD4, and amplification of E2F1, EGFR, and HER2. HPV− tumours, on the other hand, also showed mutations frequently in NRF2 and KEAP1 which are important regulators of oxidative stress.