A study led by Weber J. et al. (2015) introduced mutations in a set of tumor suppressor genes often altered in human ICC/HCC such as Arid1a, Pten, Smad4, Trp53, Apc, Cdkn2a, and in a few rarely mutated genes including Tet2, Brca1/2, in mice by conducting multiplex CRISPR/Cas9 gene editing. This evidence concerns the gene SMAD4 and intrahepatic cholangiocarcinoma.