Abstract
Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide and shows a propensity to metastasize and infiltrate adjacent and more distant tissues1. HCC is associated with multiple risk factors, including hepatitis B virus (HBV) infection, which is especially prevalent in China. Here, we used exome sequencing to identify somatic mutations in ten HBV-positive individuals with HCC with portal vein tumor thromboses (PVTTs), intrahepatic metastases. Both C:G>A:T and T:A>A:T transversions were frequently found among the 331 non-silent mutations. Notably, ARID1A, which encodes a component of the SWI/SNF chromatin remodeling complex, was mutated in 14 of 110 (13%) HBV-associated HCC specimens. We used RNA interference to assess the roles of 91 of the confirmed mutated genes in cellular survival. The results suggest that seven of these genes, including VCAM1 and CDK14, may confer growth and infiltration capacity to HCC cells. This study provides a view of the landscape of somatic mutations that may be implicated in advanced HCC.
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Acknowledgements
We gratefully acknowledge support from the Chinese National Key Program on Basic Research (2010CB529204 and 2010CB529206), the China National Key Projects for Infectious Disease (2012ZX10002012-008), the National Natural Science Foundation of China (81071722 and 81101875), the Shanghai Commission for Science and Technology (11ZR1425300), the International Scientific Collaborative Project (2011ZR0001) and the National High Technology Research and Development Program of China (863 Program, 2012AA02A205 and SS2012AA020103).
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Z.-G.H. conceived and designed the study. Q.D., J.H., Z.-D.Z. and H.-S.X. performed exome sequencing and analyzed the sequence data set. Q.D., Q.W., K.-Y.L., J.-H.D., R.-F.L. and H.C. evaluated mutations in HCC samples. Q.D. and N.L. performed large-scale RNA interference against mutated genes. Q.D., Q.W., K.-Y.L., N.L., Bo Zhou, X.-Y.L. and Q.-L.F. performed in vitro experiments on individual genes. B.C., Boping Zhou and L.-X.Q. contributed HCC samples. Z.-G.H. and Q.D. integrated, analyzed and interpreted all data. Z.-G.H. contributed to the supervision of the work. Z.-G.H. and Q.D. wrote the manuscript. All authors read and approved the final version of the manuscript.
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Supplementary Text and Figures
Supplementary Note, Supplementary Figures 1–17 and Supplementary Tables 1, 2, 6 and 8–14 (PDF 3710 kb)
Supplementary Table 3
Potential somatic base substitution mutations were identified using massively parallel sequencings (XLSX 110 kb)
Supplementary Table 4
The 682 potential non-silent somatic mutations identified using massively parallel sequencings (XLSX 93 kb)
Supplementary Table 5
The 347 genes harboring non-silent SNVs and indel mutations (XLSX 66 kb)
Supplementary Table 7
The mutation patterns between the primary tumors and the matched PVTTs (XLSX 67 kb)
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Huang, J., Deng, Q., Wang, Q. et al. Exome sequencing of hepatitis B virus–associated hepatocellular carcinoma. Nat Genet 44, 1117–1121 (2012). https://doi.org/10.1038/ng.2391
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DOI: https://doi.org/10.1038/ng.2391
