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Bin Tean Teh, Patrick Tan, Steven Rozen, Irinel Popescu and colleagues report exome sequencing of cholangiocarcinomas, including cases caused by liver fluke ( Opisthorchis viverrini ) infection and cases caused by non– O. viverrini etiologies. They identify recurrent somatic mutations in BAP1 and ARID1A and demonstrate different mutation patterns in liver fluke infection–related and non-infection-related cancers. The impact of different carcinogenic exposures on the specific patterns of somatic mutation in human tumors remains unclear. To address this issue, we profiled 209 cholangiocarcinomas (CCAs) from Asia and Europe, including 108 cases caused by infection with the liver fluke Opisthorchis viverrini and 101 cases caused by non– O. viverrini –related etiologies. Whole-exome sequencing ( n = 15) and prevalence screening ( n = 194) identified recurrent somatic mutations in BAP1 and ARID1A , neither of which, to our knowledge, has previously been reported to be mutated in CCA. Comparisons between intrahepatic O. viverrini –related and non– O. viverrini –related CCAs demonstrated statistically significant differences in mutation patterns: BAP1 , IDH1 and IDH2 were more frequently mutated in non– O. viverrini CCAs, whereas TP53 mutations showed the reciprocal pattern. Functional studies demonstrated tumor suppressive functions for BAP1 and ARID1A , establishing the role of chromatin modulators in CCA pathogenesis. These findings indicate that different causative etiologies may induce distinct somatic alterations, even within the same tumor type.

Nonetheless, heavy, long-standing infection is associated with a number of hepatobiliary diseases, including cholangitis, obstructive jaundice, hepatomegaly, fibrosis of the periportal system, cholecystitis, and cholelithiasis [7-10]. [...]both experimental and epidemiologic evidence strongly implicates liver fluke infection in the aetiology of one of the liver cancer subtypes--cholangiocarcinoma (CCA), or cancer of the bile ducts [2,11]. Unfortunately, age-old culinary preferences for uncooked dishes such as koi-pla (Figure 1) do not readily allow for this possibility. [...]fish farming of grass carp and other susceptible species in ponds that are routinely contaminated by untreated sewage has resulted in the establishment of infection in fish populations at large, which, along with the involvement of animal reservoir hosts, makes control of liver fluke infection even more challenging [13,72].