title: Genomic sequencing of colorectal adenocarcinomas identifies a recurrent VTI1A-TCF7L2 fusion.
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.
authors: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.|Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA.|Center for Cancer Genome Discovery, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.|Broad Institute, Cambridge, Massachusetts, USA.
authors: Adam J
authors: AJ
authors: Bass
authors: Broad Institute, Cambridge, Massachusetts, USA.
authors: Michael S
authors: MS
authors: Lawrence
authors: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
authors: Lear E
authors: LE
authors: Brace
authors: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.|Broad Institute, Cambridge, Massachusetts, USA.
authors: Alex H
authors: AH
authors: Ramos
authors: Department of Physics of Complex Systems, Weizmann Institute of Science, Rehovot, Israel.
authors: Yotam
authors: Y
authors: Drier
authors: Broad Institute, Cambridge, Massachusetts, USA.
authors: Kristian
authors: K
authors: Cibulskis
authors: Broad Institute, Cambridge, Massachusetts, USA.
authors: Carrie
authors: C
authors: Sougnez
authors: Broad Institute, Cambridge, Massachusetts, USA.
authors: Douglas
authors: D
authors: Voet
authors: Broad Institute, Cambridge, Massachusetts, USA.
authors: Gordon
authors: G
authors: Saksena
authors: Broad Institute, Cambridge, Massachusetts, USA.
authors: Andrey
authors: A
authors: Sivachenko
authors: Broad Institute, Cambridge, Massachusetts, USA.
authors: Rui
authors: R
authors: Jing
authors: Broad Institute, Cambridge, Massachusetts, USA.
authors: Melissa
authors: M
authors: Parkin
authors: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.|Broad Institute, Cambridge, Massachusetts, USA.
authors: Trevor
authors: T
authors: Pugh
authors: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.|Broad Institute, Cambridge, Massachusetts, USA.
authors: Roel G
authors: RG
authors: Verhaak
authors: Broad Institute, Cambridge, Massachusetts, USA.
authors: Nicolas
authors: N
authors: Stransky
authors: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
authors: Adam T
authors: AT
authors: Boutin
authors: Broad Institute, Cambridge, Massachusetts, USA.
authors: Jordi
authors: J
authors: Barretina
authors: Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, New York, New York, USA.
authors: David B
authors: DB
authors: Solit
authors: Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, New York, USA.
authors: Evi
authors: E
authors: Vakiani
authors: Novartis Institute of Biomedical Research, Cambridge, Massachusetts, USA.
authors: Wenlin
authors: W
authors: Shao
authors: Novartis Institute of Biomedical Research, Cambridge, Massachusetts, USA.
authors: Yuji
authors: Y
authors: Mishina
authors: Novartis Institute of Biomedical Research, Cambridge, Massachusetts, USA.
authors: Markus
authors: M
authors: Warmuth
authors: Department of Medical Oncology, Hospital Vall d'Hebron, Passeig Vall d'Hebron, Barcelona, Spain.
authors: Jose
authors: J
authors: Jimenez
authors: Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
authors: Derek Y
authors: DY
authors: Chiang
authors: Department of Pathology, Harvard Medical School, Boston, Massachusetts, USA.|Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts, USA.
authors: Sabina
authors: S
authors: Signoretti
authors: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.|Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA.
authors: William G
authors: WG
authors: Kaelin
authors: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
authors: Nicole
authors: N
authors: Spardy
authors: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.|Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA.|Center for Cancer Genome Discovery, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.|Broad Institute, Cambridge, Massachusetts, USA.
authors: William C
authors: WC
authors: Hahn
authors: Broad Institute, Cambridge, Massachusetts, USA.
authors: Yujin
authors: Y
authors: Hoshida
authors: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.|Department of Pathology, Harvard Medical School, Boston, Massachusetts, USA.|Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts, USA.|Channing Laboratory, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA.
authors: Shuji
authors: S
authors: Ogino
authors: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.|Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA.|Department of Genetics, Harvard Medical School, Boston, Massachusetts, USA.|Belfer Institute for Applied Cancer Science, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
authors: Ronald A
authors: RA
authors: DePinho
authors: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.|Broad Institute, Cambridge, Massachusetts, USA.|Belfer Institute for Applied Cancer Science, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.|Department of Dermatology, Harvard Medical School, Boston, Massachusetts, USA.
authors: Lynda
authors: L
authors: Chin
authors: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.|Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA.|Center for Cancer Genome Discovery, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.|Broad Institute, Cambridge, Massachusetts, USA.
authors: Levi A
authors: LA
authors: Garraway
authors: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.|Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA.|Channing Laboratory, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA.
authors: Charles S
authors: CS
authors: Fuchs
authors: Department of Medical Oncology, Hospital Vall d'Hebron, Passeig Vall d'Hebron, Barcelona, Spain.|Division of Hematology and Oncology, Massachusetts General Hospital, Boston, Massachusetts, USA.
authors: Jose
authors: J
authors: Baselga
authors: Department of Medical Oncology, Hospital Vall d'Hebron, Passeig Vall d'Hebron, Barcelona, Spain.
authors: Josep
authors: J
authors: Tabernero
authors: Broad Institute, Cambridge, Massachusetts, USA.
authors: Stacey
authors: S
authors: Gabriel
authors: Broad Institute, Cambridge, Massachusetts, USA.|Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.|Whitehead Institute for Biomedical Research, Cambridge, Massachusetts, USA.
authors: Eric S
authors: ES
authors: Lander
authors: Broad Institute, Cambridge, Massachusetts, USA.
authors: Gad
authors: G
authors: Getz
authors: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.|Center for Cancer Genome Discovery, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.|Broad Institute, Cambridge, Massachusetts, USA.|Department of Pathology, Harvard Medical School, Boston, Massachusetts, USA.
authors: Matthew
authors: M
authors: Meyerson
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics* / Q000473:pathology; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000473:pathology; D005091:Exons; D017353:Gene Deletion; D018628:Gene Dosage; D055785:Gene Knockdown Techniques; D015321:Gene Rearrangement; D015894:Genome, Human; D006801:Humans; D015514:Oncogene Proteins, Fusion; D050766:Qb-SNARE Proteins / Q000235:genetics* / Q000378:metabolism; D034622:RNA Interference; D016415:Sequence Alignment; D017422:Sequence Analysis, DNA; D000073940:Transcription Factor 4; D058118:Transcription Factor 7-Like 2 Protein / Q000235:genetics* / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism
chemical_list: D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D015514:Oncogene Proteins, Fusion; D050766:Qb-SNARE Proteins; C532096:TCF4 protein, human; C544894:TCF7L2 protein, human; D000073940:Transcription Factor 4; D058118:Transcription Factor 7-Like 2 Protein; D014157:Transcription Factors; C491419:VTI1A protein, human; D051176:beta Catenin