Recurrent R-spondin fusions in colon cancer.
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.
Department of Molecular Biology, Genentech Inc., 1 DNA Way, South San Francisco, California 94080, USA. sekar@gene.com
Somasekar
S
Seshagiri
Eric W
EW
Stawiski
Steffen
S
Durinck
Zora
Z
Modrusan
Elaine E
EE
Storm
Caitlin B
CB
Conboy
Subhra
S
Chaudhuri
Yinghui
Y
Guan
Vasantharajan
V
Janakiraman
Bijay S
BS
Jaiswal
Joseph
J
Guillory
Connie
C
Ha
Gerrit J P
GJ
Dijkgraaf
Jeremy
J
Stinson
Florian
F
Gnad
Melanie A
MA
Huntley
Jeremiah D
JD
Degenhardt
Peter M
PM
Haverty
Richard
R
Bourgon
Weiru
W
Wang
Hartmut
H
Koeppen
Robert
R
Gentleman
Timothy K
TK
Starr
Zemin
Z
Zhang
David A
DA
Largaespada
Thomas D
TD
Wu
Frederic J
FJ
de Sauvage
D064007:Ataxia Telangiectasia Mutated Proteins; D001483:Base Sequence; D018797:Cell Cycle Proteins / Q000235:genetics; D003110:Colonic Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D056915:DNA Copy Number Variations / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics; D049308:Dioxygenases / Q000235:genetics; D059472:Exome / Q000235:genetics; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D050939:Gene Fusion / Q000235:genetics*; D017491:Genes, APC; D052138:Genes, Neoplasm / Q000235:genetics*; D006801:Humans; D007335:Insulin-Like Growth Factor II / Q000235:genetics; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics*; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D017346:Protein Serine-Threonine Kinases / Q000235:genetics; D011518:Proto-Oncogene Proteins / Q000235:genetics; D020893:Receptor, ErbB-3 / Q000235:genetics; D017423:Sequence Analysis, RNA; D015398:Signal Transduction / Q000235:genetics; D019699:Thrombospondins / Q000235:genetics*; D058118:Transcription Factor 7-Like 2 Protein / Q000235:genetics; D025521:Tumor Suppressor Proteins / Q000235:genetics; D051153:Wnt Proteins / Q000378:metabolism; D000098907:R-Spondins
D064007:Ataxia Telangiectasia Mutated Proteins; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D049308:Dioxygenases; D007335:Insulin-Like Growth Factor II; D036341:Intercellular Signaling Peptides and Proteins; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D020893:Receptor, ErbB-3; D019699:Thrombospondins; D058118:Transcription Factor 7-Like 2 Protein; D025521:Tumor Suppressor Proteins; D051153:Wnt Proteins; C035170:IGF2 protein, human; C475438:RSPO3 protein, human; D000098907:R-Spondins; C557408:Rspo2 protein, human; C544894:TCF7L2 protein, human; C578792:TET3 protein, human; C541081:TET2 protein, human; C576324:ATM protein, human