Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

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

Abstract

Prior studies have identified recurrent oncogenic mutations in colorectal adenocarcinoma1 and have surveyed exons of protein-coding genes for mutations in 11 affected individuals2,3. 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-catenin4 in colorectal carcinogenesis5,6, 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.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1: DNA structural rearrangements and copy number alterations detected in the nine colorectal tumors displayed as CIRCOS plots33.
Figure 2: Complex rearrangements between chromosome pairs in two colorectal carcinomas.
Figure 3: Recurrent gene fusion between VTI1A and TCF7L2.

References

  1. Fearon, E.R. & Vogelstein, B. A genetic model for colorectal tumorigenesis. Cell 61, 759–767 (1990).

    Article  CAS  PubMed Central  Google Scholar 

  2. Sjöblom, T. et al. The consensus coding sequences of human breast and colorectal cancers. Science 314, 268–274 (2006).

    Article  Google Scholar 

  3. Wood, L.D. et al. The genomic landscapes of human breast and colorectal cancers. Science 318, 1108–1113 (2007).

    Article  CAS  Google Scholar 

  4. Clevers, H. Wnt/B-Catenin signaling in development and disease. Cell 127, 469–480 (2006).

    Article  CAS  Google Scholar 

  5. Nishisho, I. et al. Mutations of chromsome 5q21 genes in FAP and colorectal cancer patients. Science 253, 665–669 (1991).

    Article  CAS  Google Scholar 

  6. Kinzler, K.W. et al. Identification of FAP locus genes from chromosome 5q21. Science 253, 661–665 (1991).

    Article  CAS  Google Scholar 

  7. Markowitz, S.D. & Bertagnolli, M.M. Molecular basis of colorectal cancer. N. Engl. J. Med. 361, 2449–2460 (2009).

    Article  CAS  PubMed Central  Google Scholar 

  8. Ogino, S. & Goel, A. Molecular classification and correlates in colorectal cancer. J. Mol. Diagn. 10, 13–27 (2008).

    Article  CAS  PubMed Central  Google Scholar 

  9. The Cancer Genome Atlas Research Network. Integrated genomic analyses of ovarian carcinoma. Nature 474, 609–615 (2011).

  10. Berger, M.F. et al. The genomic complexity of primary human prostate cancer. Nature 470, 214–220 (2011).

    Article  CAS  PubMed Central  Google Scholar 

  11. Chapman, M. et al. Initial genome sequencing and analysis of multiple myeloma. Nature 471, 467–472 (2011).

    Article  CAS  PubMed Central  Google Scholar 

  12. Lee, W. et al. The mutation spectrum revealed by paired genome sequences from a lung cancer patient. Nature 465, 473–477 (2010).

    Article  CAS  Google Scholar 

  13. Pleasance, E.D. et al. A comprehensive catalogue of somatic mutations from a human cancer genome. Nature 463, 191–196 (2010).

    Article  CAS  PubMed Central  Google Scholar 

  14. Boland, C.R. et al. A National Cancer Institute workshop on microsatellite instability for cancer detection and familial predisposition: development of international criteria for the determination of microsatellite instability in colorectal cancer. Cancer Res. 58, 5248–5257 (1998).

    CAS  PubMed  Google Scholar 

  15. Stephens, P.J. et al. Complex landscapes of somatic rearrangement in human breast cancer genomes. Nature 462, 1005–1010 (2009).

    Article  CAS  PubMed Central  Google Scholar 

  16. Stephens, P.J. et al. Massive genomic rearrangement acquired in a single catastrophic event during cancer development. Cell 144, 27–40 (2011).

    Article  CAS  PubMed Central  Google Scholar 

  17. Bignell, G.R. et al. Signatures of mutation and selection in the cancer genome. Nature 463, 893–898 (2010).

    Article  CAS  PubMed Central  Google Scholar 

  18. Beroukhim, R. et al. The landscape of somatic copy-number alteration across human cancers. Nature 463, 899–905 (2010).

    Article  CAS  PubMed Central  Google Scholar 

  19. Soda, M. et al. Identification of the transforming EML4-ALK fusion gene in non-small cell lung cancer. Nature 448, 561–566 (2007).

    Article  CAS  Google Scholar 

  20. Tomlins, S.A. et al. Recurrent fusion of TMPRSS2 and ETS transcription factor genes in prostate cancer. Science 310, 644–648 (2005).

    Article  CAS  Google Scholar 

  21. Kreykenbohm, V. et al. The SNAREs vti1a and vti1b have distinct localization and SNARE complex partners. Eur. J. Cell Biol. 81, 273–280 (2002).

    Article  CAS  PubMed Central  Google Scholar 

  22. Waterman, M.L. Lymphoid enhancer factor/T cell factor expression in colorectal cancer. Cancer Metastasis Rev. 23, 41–52 (2004).

    Article  CAS  PubMed Central  Google Scholar 

  23. Korinek, V. et al. Constitutive transcriptional activation by a β-Catenin-Tcf complex in APC−/− colon carcinoma. Science 275, 1784–1787 (1997).

    Article  CAS  Google Scholar 

  24. Kriegl, L. et al. LEF-1 and TCF4 expression correlate inversely with survival in colorectal cancer. J. Transl. Med. 8, 123 (2010).

    Article  PubMed Central  Google Scholar 

  25. Folsom, A.R. et al. Variation in TCF7L2 and increased risk of colon cancer: the Atherosclerosis Risk in Communities (ARIC) Study. Diabetes Care 31, 905–909 (2008).

    Article  PubMed Central  Google Scholar 

  26. Hazra, A. et al. Association of the TCF7L2 polymorphism with colorectal cancer and adenoma risk. Cancer Causes Control 19, 975–980 (2008).

    Article  PubMed Central  Google Scholar 

  27. Tuupanen, S. et al. The common colorectal cancer predisposition SNP rs6983267 at chromosome 8q24 confers potential to enhanced Wnt signaling. Nat. Genet. 41, 885–890 (2009).

    Article  CAS  Google Scholar 

  28. Pomerantz, M.M. et al. The 8q24 cancer risk variant rs6983267 shows long-range interaction with MYC in colorectal cancer. Nat. Genet. 41, 882–884 (2009).

    Article  CAS  PubMed Central  Google Scholar 

  29. Roose, J. et al. Synergy between tumor suppressor APC and the B-Catenin-Tcf4 target Tcf1. Science 285, 1923–1926 (1999).

    Article  CAS  PubMed Central  Google Scholar 

  30. Van de Wetering, M. et al. The β-Catenin/TCF-4 complex imposes a crypt progenitor phenotype on colorectal cancer cells. Cell 111, 241–250 (2002).

    Article  CAS  PubMed Central  Google Scholar 

  31. Tang, W. et al. A genome-wide RNAi screen for Wnt/B-catenin pathway components identifies unexpected roles for TCF transcription factors in cancer. Proc. Natl. Acad. Sci. USA 105, 9697–9702 (2008).

    Article  CAS  Google Scholar 

  32. Angus-Hill, M.L. et al. T-cell factor 4 functions as a tumor suppressor whose disruption modulates colon cell proliferation and tumorigenesis. Proc. Natl. Acad. Sci. USA 108, 4914–4919 (2011).

    Article  CAS  Google Scholar 

  33. Krzywinski, M. et al. Circos: an informative aesthetic for comparative genomics. Genome Res. 19, 1639–1645 (2009).

    Article  CAS  PubMed Central  Google Scholar 

  34. Firestein, R. et al. CDK8 is a colorectal cancer oncogene that regulates β-catenin activity. Nature 455, 547–551 (2008).

    Article  CAS  PubMed Central  Google Scholar 

  35. The Cancer Genome Atlas Research Network. Comprehensive genomic characterization defines human glioblastoma genes and core pathways. Nature 455, 1061–1068 (2008).

  36. Chiang, D.Y. et al. High-resolution mapping of copy-number alterations with massively parallel sequencing. Nat. Methods 6, 99–103 (2009).

    Article  CAS  Google Scholar 

  37. Ley, T.J. et al. DNA sequencine of a cytogenetically normal acute myeloid leukemia genome. Nature 456, 66–72 (2008).

    Article  CAS  PubMed Central  Google Scholar 

  38. Moffat, J. et al. A lentiviral RNAi library for human and mouse genes applied to an arrayed viral high-content screen. Cell 124, 1283–1298 (2006).

    Article  CAS  Google Scholar 

  39. Bass, A.J. et al. SOX2 is an amplified lineage-survival oncogene in lung and esophageal squamous cell carcinoma. Nat. Genet. 41, 1238–1242 (2009).

    Article  CAS  PubMed Central  Google Scholar 

Download references

Acknowledgements

We thank all members of the Biological Samples Platform and DNA Sequencing Platforms of the Broad Institute, without whose work this sequencing project could not have occurred, and R. Shivdasani and M. Freedman for helpful discussion. This work was supported by US National Institutes of Health grant K08CA134931 (A.J.B.), a GI SPORE Developmental Project Award (P50CA127003; M.M.) and the National Human Genome Research Institute (E.S.L.).

Author information

Authors and Affiliations

Authors

Contributions

A.J.B., M.S.L., A.H.R., Y.D., K.C., A.S., T.P., R.J., D.V., G.S., R.G.V. and N. Stransky performed computational analysis. J. Barretina, J. Baselga, J.J., J.T., D.B.S., E.V., D.Y.C., W.G.K. and S.S. provided samples for analysis. A.J.B., L.E.B., Y.M. and W.S. performed laboratory experiments. A.T.B., Y.H., M.W., N.S., R.A.D., W.C.H., C.S.F. and S.O. provided expert guidance regarding the analysis. C.S., M.P., L.C., L.A.G., S.G. and E.S.L. supervised and designed the sequencing effort. A.J.B., M.S.L., E.S.L., G.G. and M.M. designed the study, analyzed the data and prepared the manuscript. All coauthors reviewed and commented on the manuscript.

Corresponding authors

Correspondence to Gad Getz or Matthew Meyerson.

Ethics declarations

Competing interests

M.M., L.A.G. and E.S.L. are equity-holding founding advisors of Foundation Medicine. M.M. and L.A.G. consult for Novartis. M.M. is also a patent holder on the use of EGFR mutations in lung cancer licensed to Genzyme Genetics. W.S., Y.M. and M.W. are employees of Novartis.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1 and 2, Supplementary Tables 2, 3 and 5 and Supplementary Note. (PDF 882 kb)

Supplementary Table 1

Non-synonymous Mutations and Insertions/Deletions Identified Within Coding Genes (XLSX 185 kb)

Supplementary Table 4

Somatic Rearrangements Identified with dRanger Algorithm (XLSX 146 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Bass, A., Lawrence, M., Brace, L. et al. Genomic sequencing of colorectal adenocarcinomas identifies a recurrent VTI1A-TCF7L2 fusion. Nat Genet 43, 964–968 (2011). https://doi.org/10.1038/ng.936

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ng.936

This article is cited by

Search

Quick links

Nature Briefing: Cancer

Sign up for the Nature Briefing: Cancer newsletter — what matters in cancer research, free to your inbox weekly.

Get what matters in cancer research, free to your inbox weekly. Sign up for Nature Briefing: Cancer