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Nat Genet. 2011 Sep 4;43(10):964-968. doi: 10.1038/ng.936.

Genomic sequencing of colorectal adenocarcinomas identifies a recurrent VTI1A-TCF7L2 fusion.

Author information

1
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
2
Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA.
3
Center for Cancer Genome Discovery, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
4
Broad Institute, Cambridge, Massachusetts, USA.
5
Department of Physics of Complex Systems, Weizmann Institute of Science, Rehovot, Israel.
6
Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, New York, New York, USA.
7
Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, New York, USA.
8
Novartis Institute of Biomedical Research, Cambridge, Massachusetts, USA.
9
Department of Medical Oncology, Hospital Vall d'Hebron, Passeig Vall d'Hebron, Barcelona, Spain.
10
Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
11
Department of Pathology, Harvard Medical School, Boston, Massachusetts, USA.
12
Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts, USA.
13
Channing Laboratory, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA.
14
Department of Genetics, Harvard Medical School, Boston, Massachusetts, USA.
15
Belfer Institute for Applied Cancer Science, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
16
Department of Dermatology, Harvard Medical School, Boston, Massachusetts, USA.
17
Division of Hematology and Oncology, Massachusetts General Hospital, Boston, Massachusetts, USA.
18
Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.
19
Whitehead Institute for Biomedical Research, Cambridge, Massachusetts, USA.
#
Contributed equally

Abstract

Prior studies have identified recurrent oncogenic mutations in colorectal adenocarcinoma and have surveyed exons of protein-coding genes for mutations in 11 affected individuals. Here we report whole-genome sequencing from nine individuals with colorectal cancer, including primary colorectal tumors and matched adjacent non-tumor tissues, at an average of 30.7× and 31.9× coverage, respectively. We identify an average of 75 somatic rearrangements per tumor, including complex networks of translocations between pairs of chromosomes. Eleven rearrangements encode predicted in-frame fusion proteins, including a fusion of VTI1A and TCF7L2 found in 3 out of 97 colorectal cancers. Although TCF7L2 encodes TCF4, which cooperates with β-catenin in colorectal carcinogenesis, the fusion lacks the TCF4 β-catenin-binding domain. We found a colorectal carcinoma cell line harboring the fusion gene to be dependent on VTI1A-TCF7L2 for anchorage-independent growth using RNA interference-mediated knockdown. This study shows previously unidentified levels of genomic rearrangements in colorectal carcinoma that can lead to essential gene fusions and other oncogenic events.

PMID:
21892161
PMCID:
PMC3802528
DOI:
10.1038/ng.936
[Indexed for MEDLINE]
Free PMC Article

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