Publication Date:
2012-08-17
Description:
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.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3690621/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉 〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3690621/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Seshagiri, Somasekar -- Stawiski, Eric W -- Durinck, Steffen -- Modrusan, Zora -- Storm, Elaine E -- Conboy, Caitlin B -- Chaudhuri, Subhra -- Guan, Yinghui -- Janakiraman, Vasantharajan -- Jaiswal, Bijay S -- Guillory, Joseph -- Ha, Connie -- Dijkgraaf, Gerrit J P -- Stinson, Jeremy -- Gnad, Florian -- Huntley, Melanie A -- Degenhardt, Jeremiah D -- Haverty, Peter M -- Bourgon, Richard -- Wang, Weiru -- Koeppen, Hartmut -- Gentleman, Robert -- Starr, Timothy K -- Zhang, Zemin -- Largaespada, David A -- Wu, Thomas D -- de Sauvage, Frederic J -- R00 CA151672/CA/NCI NIH HHS/ -- R01 CA134759/CA/NCI NIH HHS/ -- R01-CA134759/CA/NCI NIH HHS/ -- T32 CA009138/CA/NCI NIH HHS/ -- England -- Nature. 2012 Aug 30;488(7413):660-4. doi: 10.1038/nature11282.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Molecular Biology, Genentech Inc., 1 DNA Way, South San Francisco, California 94080, USA. sekar@gene.com〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22895193" target="_blank"〉PubMed〈/a〉
Keywords:
Ataxia Telangiectasia Mutated Proteins
;
Base Sequence
;
Cell Cycle Proteins/genetics
;
Colonic Neoplasms/*genetics/metabolism/pathology
;
DNA Copy Number Variations/genetics
;
DNA-Binding Proteins/genetics
;
Dioxygenases/genetics
;
Exome/genetics
;
Gene Expression Profiling
;
Gene Expression Regulation, Neoplastic/genetics
;
Gene Fusion/*genetics
;
Genes, APC
;
Genes, Neoplasm/*genetics
;
Humans
;
Insulin-Like Growth Factor II/genetics
;
Intercellular Signaling Peptides and Proteins/*genetics
;
Molecular Sequence Data
;
Mutation/genetics
;
Polymorphism, Single Nucleotide/genetics
;
Protein-Serine-Threonine Kinases/genetics
;
Proto-Oncogene Proteins/genetics
;
Receptor, ErbB-3/genetics
;
Sequence Analysis, RNA
;
Signal Transduction/genetics
;
Thrombospondins/*genetics
;
Transcription Factor 7-Like 2 Protein/genetics
;
Tumor Suppressor Proteins/genetics
;
Wnt Proteins/metabolism
Print ISSN:
0028-0836
Electronic ISSN:
1476-4687
Topics:
Biology
,
Chemistry and Pharmacology
,
Medicine
,
Natural Sciences in General
,
Physics
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