Exome sequencing of liver fluke-associated cholangiocarcinoma

Opisthorchis viverrini related cholangiocarcinoma (CCA), a fatal bile duct cancer, is a major public health problem in O. viverrini endemic areas. To gain insights into this cancer’s mutation landscape, exomic sequences of eight O. viverrini-related paired tumors were examined, followed by prevalence screening in an additional 46 cases. Besides known cancer related genes TP53 (44.4%), KRAS (16.7%) and SMAD4 (16.7%), 10 other genes which have never been implicated in CCA were somatically mutated in 14.8%-3.7% of cases. These include inactivating mutations in MLL3 (14.8%), ROBO2 (9.3%), RNF43 (9.3%), PEG3 (5.6%) and activating mutations of GNAS oncogene (9.3%). Taken together, these genes can be broadly grouped into 3 biological themes: (i) deactivation of histone modifiers, (ii) activation of G-protein signaling and (iii) loss of genome stability. This study sheds light on the molecular mechanisms of O. viverrini-related CCA, paving the way for further studies on their roles in CCA tumorigenesis.