SMAD4 and neoplasm: In addition to the above key genes affected, de novo mutations occurring in liver or lung metastases of case-matched tumours in at least 3 cases were in APC, ATM, FBXW7, FGFR3, GNAQ, KIT, PIK3CA, PTEN, SMAD4, SMO, STK11, TP53 and VHL. Thereby, synchronous vs metachronous as well as liver vs lung metastases displayed distinct gene patterns suggesting distinct tumour evolution.