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: 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
• Journal: Nature genetics (Nat Genet) Vol. 43 Issue 10 Pg. 964-968 (Sep 04 2011) ISSN: 1546-1718 [Electronic] United States
• PMID: 21892161 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• 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

Topics

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