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