Recurrent R-spondin fusions in colon cancer

Somasekar Seshagiri; Eric W. Stawiski; Steffen Durinck; Zora Modrusan; Elaine E. Storm; Caitlin B. Conboy; Subhra Chaudhuri; Yinghui Guan; Vasantharajan Janakiraman; Bijay S. Jaiswal; Joseph Guillory; Connie Ha; Gerrit J.P. Dijkgraaf; Jeremy Stinson; Florian Gnad; Melanie A. Huntley; Jeremiah D. Degenhardt; Peter M. Haverty; Richard Bourgon; Weiru Wang; Hartmut Koeppen; Robert Gentleman; Timothy K. Starr; Zemin Zhang; David A. Largaespada; Thomas D. Wu; Frederic J. De Sauvage

doi:10.1038/nature11282

Recurrent R-spondin fusions in colon cancer

Somasekar Seshagiri, Eric W. Stawiski, Steffen Durinck, Zora Modrusan, Elaine E. Storm, Caitlin B. Conboy, Subhra Chaudhuri, Yinghui Guan, Vasantharajan Janakiraman, Bijay S. Jaiswal, Joseph Guillory, Connie Ha, Gerrit J.P. Dijkgraaf, Jeremy Stinson, Florian Gnad, Melanie A. Huntley, Jeremiah D. Degenhardt, Peter M. Haverty, Richard Bourgon, Weiru WangHartmut Koeppen, Robert Gentleman, Timothy K. Starr, Zemin Zhang, David A. Largaespada, Thomas D. Wu, Frederic J. De Sauvage

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836 Scopus citations

Abstract

Identifying and understanding changes in cancer genomes is essential for the development of targeted therapeutics. Here we analyse systematically more than 70 pairs of primary human colon tumours by applying next-generation sequencing to characterize their exomes, transcriptomes and copy-number alterations. We have identified 36,303 protein-altering somatic changes that include several new recurrent mutations in the Wnt pathway gene TCF7L2, chromatin-remodelling genes such as TET2 and TET3 and receptor tyrosine kinases including ERBB3. Our analysis for significantly mutated cancer genes identified 23 candidates, including the cell cycle checkpoint kinase ATM. Copy-number and RNA-seq data analysis identified amplifications and corresponding overexpression of IGF2 in a subset of colon tumours. Furthermore, using RNA-seq data we identified multiple fusion transcripts including recurrent gene fusions involving R-spondin family members RSPO2 and RSPO3 that together occur in 10% of colon tumours. The RSPO fusions were mutually exclusive with APC mutations, indicating that they probably have a role in the activation of Wnt signalling and tumorigenesis. Consistent with this we show that the RSPO fusion proteins were capable of potentiating Wnt signalling. The R-spondin gene fusions and several other gene mutations identified in this study provide new potential opportunities for therapeutic intervention in colon cancer.

Original language	English (US)
Pages (from-to)	660-664
Number of pages	5
Journal	Nature
Volume	488
Issue number	7413
DOIs	https://doi.org/10.1038/nature11282
State	Published - Aug 30 2012

Bibliographical note

Funding Information:
Acknowledgements The authors would like to acknowledge Genentech DNA Sequencing, Oligo, Microarray and gCell laboratories for their help with the project. We thank the Genentech Bioinformatics group for informatics infrastructure support and the Pathology Core Labs for providing histology, immunohistochemistry and tissue-management support. We also thank M. Costa, M. Callow, P. Polakis and the de Sauvage and Seshagiri laboratories for comments and suggestions. Work in the Largaespada laboratory was supported by National Institutes of Health grant R01-CA134759 (to D.A.L.).

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Seshagiri, S., Stawiski, E. W., Durinck, S., Modrusan, Z., Storm, E. E., Conboy, C. B., Chaudhuri, S., Guan, Y., Janakiraman, V., Jaiswal, B. S., Guillory, J., Ha, C., Dijkgraaf, G. J. P., Stinson, J., Gnad, F., Huntley, M. A., Degenhardt, J. D., Haverty, P. M., Bourgon, R., ... De Sauvage, F. J. (2012). Recurrent R-spondin fusions in colon cancer. Nature, 488(7413), 660-664. https://doi.org/10.1038/nature11282

Seshagiri, S, Stawiski, EW, Durinck, S, Modrusan, Z, Storm, EE, Conboy, CB, Chaudhuri, S, Guan, Y, Janakiraman, V, Jaiswal, BS, Guillory, J, Ha, C, Dijkgraaf, GJP, Stinson, J, Gnad, F, Huntley, MA, Degenhardt, JD, Haverty, PM, Bourgon, R, Wang, W, Koeppen, H, Gentleman, R, Starr, TK, Zhang, Z, Largaespada, DA, Wu, TD & De Sauvage, FJ 2012, 'Recurrent R-spondin fusions in colon cancer', Nature, vol. 488, no. 7413, pp. 660-664. https://doi.org/10.1038/nature11282

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title = "Recurrent R-spondin fusions in colon cancer",

abstract = "Identifying and understanding changes in cancer genomes is essential for the development of targeted therapeutics. Here we analyse systematically more than 70 pairs of primary human colon tumours by applying next-generation sequencing to characterize their exomes, transcriptomes and copy-number alterations. We have identified 36,303 protein-altering somatic changes that include several new recurrent mutations in the Wnt pathway gene TCF7L2, chromatin-remodelling genes such as TET2 and TET3 and receptor tyrosine kinases including ERBB3. Our analysis for significantly mutated cancer genes identified 23 candidates, including the cell cycle checkpoint kinase ATM. Copy-number and RNA-seq data analysis identified amplifications and corresponding overexpression of IGF2 in a subset of colon tumours. Furthermore, using RNA-seq data we identified multiple fusion transcripts including recurrent gene fusions involving R-spondin family members RSPO2 and RSPO3 that together occur in 10% of colon tumours. The RSPO fusions were mutually exclusive with APC mutations, indicating that they probably have a role in the activation of Wnt signalling and tumorigenesis. Consistent with this we show that the RSPO fusion proteins were capable of potentiating Wnt signalling. The R-spondin gene fusions and several other gene mutations identified in this study provide new potential opportunities for therapeutic intervention in colon cancer.",

author = "Somasekar Seshagiri and Stawiski, {Eric W.} and Steffen Durinck and Zora Modrusan and Storm, {Elaine E.} and Conboy, {Caitlin B.} and Subhra Chaudhuri and Yinghui Guan and Vasantharajan Janakiraman and Jaiswal, {Bijay S.} and Joseph Guillory and Connie Ha and Dijkgraaf, {Gerrit J.P.} and Jeremy Stinson and Florian Gnad and Huntley, {Melanie A.} and Degenhardt, {Jeremiah D.} and Haverty, {Peter M.} and Richard Bourgon and Weiru Wang and Hartmut Koeppen and Robert Gentleman and Starr, {Timothy K.} and Zemin Zhang and Largaespada, {David A.} and Wu, {Thomas D.} and {De Sauvage}, {Frederic J.}",

note = "Funding Information: Acknowledgements The authors would like to acknowledge Genentech DNA Sequencing, Oligo, Microarray and gCell laboratories for their help with the project. We thank the Genentech Bioinformatics group for informatics infrastructure support and the Pathology Core Labs for providing histology, immunohistochemistry and tissue-management support. We also thank M. Costa, M. Callow, P. Polakis and the de Sauvage and Seshagiri laboratories for comments and suggestions. Work in the Largaespada laboratory was supported by National Institutes of Health grant R01-CA134759 (to D.A.L.).",

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AU - Seshagiri, Somasekar

AU - Stawiski, Eric W.

AU - Durinck, Steffen

AU - Modrusan, Zora

AU - Storm, Elaine E.

AU - Conboy, Caitlin B.

AU - Chaudhuri, Subhra

AU - Guan, Yinghui

AU - Janakiraman, Vasantharajan

AU - Jaiswal, Bijay S.

AU - Guillory, Joseph

AU - Ha, Connie

AU - Dijkgraaf, Gerrit J.P.

AU - Stinson, Jeremy

AU - Gnad, Florian

AU - Huntley, Melanie A.

AU - Degenhardt, Jeremiah D.

AU - Haverty, Peter M.

AU - Bourgon, Richard

AU - Wang, Weiru

AU - Koeppen, Hartmut

AU - Gentleman, Robert

AU - Starr, Timothy K.

AU - Zhang, Zemin

AU - Largaespada, David A.

AU - Wu, Thomas D.

AU - De Sauvage, Frederic J.

N1 - Funding Information: Acknowledgements The authors would like to acknowledge Genentech DNA Sequencing, Oligo, Microarray and gCell laboratories for their help with the project. We thank the Genentech Bioinformatics group for informatics infrastructure support and the Pathology Core Labs for providing histology, immunohistochemistry and tissue-management support. We also thank M. Costa, M. Callow, P. Polakis and the de Sauvage and Seshagiri laboratories for comments and suggestions. Work in the Largaespada laboratory was supported by National Institutes of Health grant R01-CA134759 (to D.A.L.).

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N2 - Identifying and understanding changes in cancer genomes is essential for the development of targeted therapeutics. Here we analyse systematically more than 70 pairs of primary human colon tumours by applying next-generation sequencing to characterize their exomes, transcriptomes and copy-number alterations. We have identified 36,303 protein-altering somatic changes that include several new recurrent mutations in the Wnt pathway gene TCF7L2, chromatin-remodelling genes such as TET2 and TET3 and receptor tyrosine kinases including ERBB3. Our analysis for significantly mutated cancer genes identified 23 candidates, including the cell cycle checkpoint kinase ATM. Copy-number and RNA-seq data analysis identified amplifications and corresponding overexpression of IGF2 in a subset of colon tumours. Furthermore, using RNA-seq data we identified multiple fusion transcripts including recurrent gene fusions involving R-spondin family members RSPO2 and RSPO3 that together occur in 10% of colon tumours. The RSPO fusions were mutually exclusive with APC mutations, indicating that they probably have a role in the activation of Wnt signalling and tumorigenesis. Consistent with this we show that the RSPO fusion proteins were capable of potentiating Wnt signalling. The R-spondin gene fusions and several other gene mutations identified in this study provide new potential opportunities for therapeutic intervention in colon cancer.

AB - Identifying and understanding changes in cancer genomes is essential for the development of targeted therapeutics. Here we analyse systematically more than 70 pairs of primary human colon tumours by applying next-generation sequencing to characterize their exomes, transcriptomes and copy-number alterations. We have identified 36,303 protein-altering somatic changes that include several new recurrent mutations in the Wnt pathway gene TCF7L2, chromatin-remodelling genes such as TET2 and TET3 and receptor tyrosine kinases including ERBB3. Our analysis for significantly mutated cancer genes identified 23 candidates, including the cell cycle checkpoint kinase ATM. Copy-number and RNA-seq data analysis identified amplifications and corresponding overexpression of IGF2 in a subset of colon tumours. Furthermore, using RNA-seq data we identified multiple fusion transcripts including recurrent gene fusions involving R-spondin family members RSPO2 and RSPO3 that together occur in 10% of colon tumours. The RSPO fusions were mutually exclusive with APC mutations, indicating that they probably have a role in the activation of Wnt signalling and tumorigenesis. Consistent with this we show that the RSPO fusion proteins were capable of potentiating Wnt signalling. The R-spondin gene fusions and several other gene mutations identified in this study provide new potential opportunities for therapeutic intervention in colon cancer.

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Recurrent R-spondin fusions in colon cancer

Abstract

Bibliographical note

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