Journal Article

Exome sequencing identifies distinct mutational patterns in liver fluke–related and non-infection-related bile duct cancers

Rajasegaran, Vikneswari, Sithithaworn, Paiboon, Yu, Willie, Huang, DaChuan, Heng, Hong Lee, Teh, Bin Tean, Duda, Dan, Yongvanit, Puangrat, Popescu, Irinel, McPherson, John R, Chow, Pierce, Khuntikeo, Narong, Bhudhisawasdi, Vajaraphongsa, Rozen, Steven G, Lee, Ser Yee, Cheow, Peng Chung, Gan, Anna, Zhang, Shenli, Chan-on, Waraporn, Chung, Alexander, Nairismägi, Maarja-Liisa, Wongkham, Sopit, Pairojkul, Chawalit, Myint, Swe Swe, Ng, Cedric Chuan Young, Ooi, London, Nagarajan, Sanjanaa, Jusakul, Apinya, Dima, Simona, Cutcutache, Ioana, Lim, Kiat Hon, Ong, Choon Kiat, Tan, Patrick, Wong, Bernice Huimin, Choo, Su Pin, Tan, Iain Bee Huat, Lim, Weng Khong, Nastase, Anca, Vohra, Priya

2013

Overview

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.

• Publisher: Nature Publishing Group US,Nature Publishing Group
• Subject: 38 / 38/1 / 38/109 / 38/77 / 45 / 45/23 / 45/61 / 45/62 / 631/208/514/1948 / 692/699/1503/1607/1610 / 692/699/67/1504/1329/1326 / Agriculture / Animal Genetics and Genomics / Animals / Bile Duct Neoplasms - genetics / Bile Duct Neoplasms - parasitology / Bile Ducts, Intrahepatic / Bioinformatics / Biomedicine / Cancer / Cancer Research / Cholangiocarcinoma - genetics / Cholangiocarcinoma - parasitology / Exome - genetics / Exome sequencing / Fasciola hepatica / Fascioliasis - complications / Female / Gene expression / Gene Frequency / Gene Function / Gene mutations / Genetic aspects / Genetic engineering / Genetic Predisposition to Disease / Genomes / Human Genetics / Humans / Hypothesis testing / Identification and classification / Infections / Isocitrate Dehydrogenase - genetics / letter / Male / Methods / Mutation / Neoplastic processes / Opisthorchis viverrini / Sequence Analysis, DNA / Studies / Trematoda / Tumor Cells, Cultured / Tumor Suppressor Proteins - genetics / Ubiquitin Thiolesterase - genetics