However, among the most frequently mutated genes in CCA, such as CDKN2A/B, IDH1/2, BAP1, BRAF, ARID1A, KRAS, TP53, TERT, SMAD4, BRCA1/2, TGFBR2, RBM10, NF1, SPTA1, RB1, KMT2C and DDR, the frequency varies according to geographical origin, patient lifestyle and the design of the mutation analysis [32,48,49]. This evidence concerns the gene SMAD4 and cholangiocarcinoma.