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

Adam J Bass; Michael S Lawrence; Lear E Brace; Alex H Ramos; Yotam Drier; Kristian Cibulskis; Carrie Sougnez; Douglas Voet; Gordon Saksena; Andrey Sivachenko; Rui Jing; Melissa Parkin; Trevor Pugh; Roel G Verhaak; Nicolas Stransky; Adam T Boutin; Jordi Barretina; David B Solit; Evi Vakiani; Wenlin Shao; Yuji Mishina; Markus Warmuth; Jose Jimenez; Derek Y Chiang; Sabina Signoretti; William G Kaelin Jr; Nicole Spardy; William C Hahn; Yujin Hoshida; Shuji Ogino; Ronald A DePinho; Lynda Chin; Levi A Garraway; Charles S Fuchs; Jose Baselga; Josep Tabernero; Stacey Gabriel; Eric S Lander; Gad Getz; Matthew Meyerson

doi:10.1038/ng.936

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

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

Authors

Adam J Bass^#^{1

2

3

4}, Michael S Lawrence^#⁴, Lear E Brace¹, Alex H Ramos^{1

4}, Yotam Drier⁵, Kristian Cibulskis⁴, Carrie Sougnez⁴, Douglas Voet⁴, Gordon Saksena⁴, Andrey Sivachenko⁴, Rui Jing⁴, Melissa Parkin⁴, Trevor Pugh^{1

4}, Roel G Verhaak^{1

4}, Nicolas Stransky⁴, Adam T Boutin¹, Jordi Barretina⁴, David B Solit⁶, Evi Vakiani⁷, Wenlin Shao⁸, Yuji Mishina⁸, Markus Warmuth⁸, Jose Jimenez⁹, Derek Y Chiang¹⁰, Sabina Signoretti^{11

12}, William G Kaelin Jr^{1

2}, Nicole Spardy¹, William C Hahn^{1

2

3

4}, Yujin Hoshida⁴, Shuji Ogino^{1

11

12

13}, Ronald A DePinho^{1

2

14

15}, Lynda Chin^{1

4

15

16}, Levi A Garraway^{1

2

3

4}, Charles S Fuchs^{1

2

13}, Jose Baselga^{9

17}, Josep Tabernero⁹, Stacey Gabriel⁴, Eric S Lander^{4

18

19}, Gad Getz⁴, Matthew Meyerson^{1

3

4

11}

Affiliations

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.

PMID: 21892161
PMCID: PMC3802528
DOI: 10.1038/ng.936

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Adenocarcinoma / genetics*
Adenocarcinoma / pathology
Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / genetics
Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / metabolism
Cell Line, Tumor
Cell Transformation, Neoplastic / genetics
Colorectal Neoplasms / genetics*
Colorectal Neoplasms / pathology
Exons
Gene Deletion
Gene Dosage
Gene Knockdown Techniques
Gene Rearrangement
Genome, Human
Humans
Oncogene Proteins, Fusion*
Qb-SNARE Proteins / genetics*
Qb-SNARE Proteins / metabolism
RNA Interference
Sequence Alignment
Sequence Analysis, DNA
Transcription Factor 4
Transcription Factor 7-Like 2 Protein / genetics*
Transcription Factor 7-Like 2 Protein / metabolism
Transcription Factors / genetics
Transcription Factors / metabolism
beta Catenin / genetics
beta Catenin / metabolism

Substances

Basic Helix-Loop-Helix Leucine Zipper Transcription Factors
Oncogene Proteins, Fusion
Qb-SNARE Proteins
TCF4 protein, human
TCF7L2 protein, human
Transcription Factor 4
Transcription Factor 7-Like 2 Protein
Transcription Factors
VTI1A protein, human
beta Catenin

Abstract

Publication types

MeSH terms

Substances

Grants and funding