POLE and cancer: Eleven percent of BTC patients harbored deleterious germline mutations of cancer-predisposing genes such as BRCA1, BRCA2, RAD51D, MLH1, MSH2, POLD1, POLE, TP53, and ATM. Interestingly, all of the hypermutated samples display somatic or germline mutations in at least one known DNA mismatch repair gene (e.g., MLH1, MSH2) or DNA polymerase (e.g., POLD1, POLE) [106].