Transposon mutagenesis identifies genes driving hepatocellular carcinoma in a chronic hepatitis B mouse model

Emilie A. Bard-Chapeau; Anh Tuan Nguyen; Alistair G. Rust; Ahmed Sayadi; Philip Lee; Belinda Q. Chua; Lee Sun New; Johann De Jong; Jerrold M. Ward; Christopher K Y Chin; Valerie Chew; Han Chong Toh; Jean Pierre Abastado; Touati Benoukraf; Richie Soong; Frederic A. Bard; Adam J. Dupuy; Randy L. Johnson; George K. Radda; Eric Chun Yong Chan; Lodewyk F A Wessels; David J. Adams; Nancy A. Jenkins; Neal G. Copeland

doi:10.1038/ng.2847

Transposon mutagenesis identifies genes driving hepatocellular carcinoma in a chronic hepatitis B mouse model

Emilie A. Bard-Chapeau, Anh Tuan Nguyen, Alistair G. Rust, Ahmed Sayadi, Philip Lee, Belinda Q. Chua, Lee Sun New, Johann De Jong, Jerrold M. Ward, Christopher K Y Chin, Valerie Chew, Han Chong Toh, Jean Pierre Abastado, Touati Benoukraf, Richie Soong, Frederic A. Bard, Adam J. Dupuy, Randy L. Johnson, George K. Radda, Eric Chun Yong ChanLodewyk F A Wessels, David J. Adams, Nancy A. Jenkins, Neal G. Copeland

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Abstract

The most common risk factor for developing hepatocellular carcinoma (HCC) is chronic infection with hepatitis B virus (HBV). To better understand the evolutionary forces driving HCC, we performed a near-saturating transposon mutagenesis screen in a mouse HBV model of HCC. This screen identified 21 candidate early stage drivers and a very large number (2,860) of candidate later stage drivers that were enriched for genes that are mutated, deregulated or functioning in signaling pathways important for human HCC, with a striking 1,199 genes being linked to cellular metabolic processes. Our study provides a comprehensive overview of the genetic landscape of HCC.

Original language	English (US)
Pages (from-to)	24-32
Number of pages	9
Journal	Nature Genetics
Volume	46
Issue number	1
DOIs	https://doi.org/10.1038/ng.2847
State	Published - Jan 2014

ASJC Scopus subject areas

Genetics

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Bard-Chapeau, E. A., Nguyen, A. T., Rust, A. G., Sayadi, A., Lee, P., Chua, B. Q., New, L. S., De Jong, J., Ward, J. M., Chin, C. K. Y., Chew, V., Toh, H. C., Abastado, J. P., Benoukraf, T., Soong, R., Bard, F. A., Dupuy, A. J., Johnson, R. L., Radda, G. K., ... Copeland, N. G. (2014). Transposon mutagenesis identifies genes driving hepatocellular carcinoma in a chronic hepatitis B mouse model. Nature Genetics, 46(1), 24-32. https://doi.org/10.1038/ng.2847

Bard-Chapeau, EA, Nguyen, AT, Rust, AG, Sayadi, A, Lee, P, Chua, BQ, New, LS, De Jong, J, Ward, JM, Chin, CKY, Chew, V, Toh, HC, Abastado, JP, Benoukraf, T, Soong, R, Bard, FA, Dupuy, AJ, Johnson, RL, Radda, GK, Chan, ECY, Wessels, LFA, Adams, DJ, Jenkins, NA & Copeland, NG 2014, 'Transposon mutagenesis identifies genes driving hepatocellular carcinoma in a chronic hepatitis B mouse model', Nature Genetics, vol. 46, no. 1, pp. 24-32. https://doi.org/10.1038/ng.2847

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title = "Transposon mutagenesis identifies genes driving hepatocellular carcinoma in a chronic hepatitis B mouse model",

abstract = "The most common risk factor for developing hepatocellular carcinoma (HCC) is chronic infection with hepatitis B virus (HBV). To better understand the evolutionary forces driving HCC, we performed a near-saturating transposon mutagenesis screen in a mouse HBV model of HCC. This screen identified 21 candidate early stage drivers and a very large number (2,860) of candidate later stage drivers that were enriched for genes that are mutated, deregulated or functioning in signaling pathways important for human HCC, with a striking 1,199 genes being linked to cellular metabolic processes. Our study provides a comprehensive overview of the genetic landscape of HCC.",

author = "Bard-Chapeau, {Emilie A.} and Nguyen, {Anh Tuan} and Rust, {Alistair G.} and Ahmed Sayadi and Philip Lee and Chua, {Belinda Q.} and New, {Lee Sun} and {De Jong}, Johann and Ward, {Jerrold M.} and Chin, {Christopher K Y} and Valerie Chew and Toh, {Han Chong} and Abastado, {Jean Pierre} and Touati Benoukraf and Richie Soong and Bard, {Frederic A.} and Dupuy, {Adam J.} and Johnson, {Randy L.} and Radda, {George K.} and Chan, {Eric Chun Yong} and Wessels, {Lodewyk F A} and Adams, {David J.} and Jenkins, {Nancy A.} and Copeland, {Neal G.}",

note = "Funding Information: We acknowledge K. Reifenberg at Johannes Gutenberg University, Germany, for giving us the HBsAg mouse strain (originated from F. Chisari). We also thank K. Rogers and S. Rogers at the Institute of Molecular and Cell Biology Histopathology core for their necropsy and histotechnology assistance. We thank P. Cheok, N. Lim and D. Chen for their help with mouse breeding and monitoring. This work was supported by the Biomedical Research Council, Agency for Science, Technology and Research, Singapore and the Cancer Prevention Research Institute of Texas (CPRIT). A.G.R. and D.J.A. are supported by the Wellcome Trust and Cancer Research UK. N.A.J. and N.G.C. are both CPRIT Scholars in Cancer Research.",

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doi = "10.1038/ng.2847",

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AU - Bard-Chapeau, Emilie A.

AU - Nguyen, Anh Tuan

AU - Rust, Alistair G.

AU - Sayadi, Ahmed

AU - Lee, Philip

AU - Chua, Belinda Q.

AU - New, Lee Sun

AU - De Jong, Johann

AU - Ward, Jerrold M.

AU - Chin, Christopher K Y

AU - Chew, Valerie

AU - Toh, Han Chong

AU - Abastado, Jean Pierre

AU - Benoukraf, Touati

AU - Soong, Richie

AU - Bard, Frederic A.

AU - Dupuy, Adam J.

AU - Johnson, Randy L.

AU - Radda, George K.

AU - Chan, Eric Chun Yong

AU - Wessels, Lodewyk F A

AU - Adams, David J.

AU - Jenkins, Nancy A.

AU - Copeland, Neal G.

N1 - Funding Information: We acknowledge K. Reifenberg at Johannes Gutenberg University, Germany, for giving us the HBsAg mouse strain (originated from F. Chisari). We also thank K. Rogers and S. Rogers at the Institute of Molecular and Cell Biology Histopathology core for their necropsy and histotechnology assistance. We thank P. Cheok, N. Lim and D. Chen for their help with mouse breeding and monitoring. This work was supported by the Biomedical Research Council, Agency for Science, Technology and Research, Singapore and the Cancer Prevention Research Institute of Texas (CPRIT). A.G.R. and D.J.A. are supported by the Wellcome Trust and Cancer Research UK. N.A.J. and N.G.C. are both CPRIT Scholars in Cancer Research.

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N2 - The most common risk factor for developing hepatocellular carcinoma (HCC) is chronic infection with hepatitis B virus (HBV). To better understand the evolutionary forces driving HCC, we performed a near-saturating transposon mutagenesis screen in a mouse HBV model of HCC. This screen identified 21 candidate early stage drivers and a very large number (2,860) of candidate later stage drivers that were enriched for genes that are mutated, deregulated or functioning in signaling pathways important for human HCC, with a striking 1,199 genes being linked to cellular metabolic processes. Our study provides a comprehensive overview of the genetic landscape of HCC.

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Transposon mutagenesis identifies genes driving hepatocellular carcinoma in a chronic hepatitis B mouse model

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