SMAD6 and cancer: We also found lines of evidence that TGFβ signaling may be frequently perturbed by somatic mutations including a nonsense TGFBR1 mutation along with additional missense mutations on TGFBR2 and inhibitory SMADs such as SMAD6 and SMAD7. Among known cancer-related genes [16], we observed splicing mutations on MSH2 and RB1 as well as a number of missense mutations on GNAS, MAP2K1, MED12, and NF1, which requires further investigation for their oncogenic potential in ICC.