TY - JOUR
T1 - Recurrent R-spondin fusions in colon cancer
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.).
PY - 2012/8/30
Y1 - 2012/8/30
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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U2 - 10.1038/nature11282
DO - 10.1038/nature11282
M3 - Article
C2 - 22895193
AN - SCOPUS:84865459654
SN - 0028-0836
VL - 488
SP - 660
EP - 664
JO - Nature
JF - Nature
IS - 7413
ER -