Opisthorchis viverrini–related cholangiocarcinoma (CCA), a fatal bile duct cancer, is a major public health concern in areas endemic for this parasite. We report here whole-exome sequencing of eight O. viverrini–related tumors and matched normal tissue. We identified and validated 206 somatic mutations in 187 genes using Sanger sequencing and selected 15 genes for mutation prevalence screening in an additional 46 individuals with CCA (cases). In addition to the known cancer-related genes TP53 (mutated in 44.4% of cases), KRAS (16.7%) and SMAD4 (16.7%), we identified somatic mutations in 10 newly implicated genes in 14.8–3.7% of cases. These included inactivating mutations in MLL3 (in 14.8% of cases), ROBO2 (9.3%), RNF43 (9.3%) and PEG3 (5.6%), and activating mutations in the GNAS oncogene (9.3%). These genes have functions that can be broadly grouped into three biological classes: (i) deactivation of histone modifiers, (ii) activation of G protein signaling and (iii) loss of genome stability. This study provides insight into the mutational landscape contributing to O. viverrini–related CCA.
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We thank L. Farber for editing the manuscript. This work is supported in part by funding from the Singapore National Medical Research Council (NMRC/STAR/0006/2009), The Singapore Millennium Foundation, The Lee Foundation, the Singapore National Cancer Centre Research Fund, the Duke-NUS Graduate Medical School, the Cancer Science Institute, Singapore, the Research Team Strengthening Grant, the National Genetic Engineering and Biotechnology Center and the National Science and Technology Development Agency, Thailand. W.Y. is the recipient of the NUS Graduate School for Integrative Sciences and Engineering Scholarship, Singapore.
The authors declare no competing financial interests.
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Ong, C., Subimerb, C., Pairojkul, C. et al. Exome sequencing of liver fluke–associated cholangiocarcinoma. Nat Genet 44, 690–693 (2012) doi:10.1038/ng.2273
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