Article

Exome sequencing of liver fluke-associated cholangiocarcinoma

National Cancer Centre Singapore-Van Andel Research Institute Translational Research Laboratory, Division of Medical Sciences, Singapore.
Nature Genetics (Impact Factor: 29.65). 05/2012; 44(6):690-3. DOI: 10.1038/ng.2273
Source: PubMed

ABSTRACT 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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    • "Targeting specific molecular pathways holds promise for advanced gallbladder cancer therapy. Cancer Treat Rev (2015), http://dx.doi.org/10.1016/j.ctrv.2015.01.003 similar to lithiasis-related GBC [18] [36] [37]. This similarity in carcinogenesis may be attributed to the chronic presence of a ''foreign'' body observed in these two anatomically associated cancers. "
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    Cancer Treatment Reviews 01/2015; 41(3). DOI:10.1016/j.ctrv.2015.01.003 · 6.47 Impact Factor
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    • "Although many frequently mutated genes have been identified in cholangiocarcinoma, such as TP53 (37–44%) and KRAS (17–54%) (4), none of these signature genes have become targets of therapy. Sequencing efforts are continuously conducted in order to generate in-depth information with regard to the somatic alterations in ICC. "
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    International Journal of Molecular Medicine 06/2014; 34(3). DOI:10.3892/ijmm.2014.1823 · 1.88 Impact Factor
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    • "In another study vandetanib, a partial EGFR inhibitor, suppressed growth of TKKK (KRAS WT) BTC cell line, while HuCCT (KRAS mutant) required 10 times the amount of drug for similar effect (Yoshikawa et al, 2009). KRAS mutations are found in 3–50% of tumours depending on tumour location and methodology used to evaluate for mutations in different studies (Suto et al, 2000; Rashid et al, 2002; Ong et al, 2012). The most recent report suggests that KRAS mutations are most common in extrahepatic tumours and that rates for intrahepatic cancers are on the lower end of this spectrum at 9–22% (Voss et al, 2013). "
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