Abstract

An inherited variant on chromosome 8q24, rs6983267, is significantly associated with cancer pathogenesis. We present evidence that the region harboring this variant is a transcriptional enhancer, that the alleles of rs6983267 differentially bind transcription factor 7-like 2 (TCF7L2) and that the risk region physically interacts with the MYC proto-oncogene. These data provide strong support for a biological mechanism underlying this non-protein-coding risk variant.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Accessions

Gene Expression Omnibus

References

  1. 1.

    et al. Nat. Genet. 39, 984–988 (2007).

  2. 2.

    et al. Nat. Genet. 39, 989–994 (2007).

  3. 3.

    et al. Nat. Genet. 39, 954–956 (2007).

  4. 4.

    et al. Hum. Genet. 124, 161–170 (2008).

  5. 5.

    et al. Nat. Genet. 39, 311–318 (2007).

  6. 6.

    et al. Nature 457, 854–858 (2009).

  7. 7.

    et al. Nat. Genet. advance online publication, doi:10.1038/ng.406 (June 2009).

  8. 8.

    & Cell 103, 311–320 (2000).

  9. 9.

    Genes Dev. 14, 1837–1851 (2000).

  10. 10.

    , & Adv. Cancer Res. 77, 1–24 (2000).

  11. 11.

    et al. Science 275, 1787–1790 (1997).

  12. 12.

    et al. Science 275, 1784–1787 (1997).

  13. 13.

    et al. Nature 446, 676–679 (2007).

  14. 14.

    , , , & Curr. Protoc. Mol. Biol. Chapter 21, Unit 21 11 (2006).

  15. 15.

    et al. J. Natl. Cancer Inst. 100, 962–966 (2008).

Download references

Acknowledgements

M.L.F. is a Howard Hughes Medical Institute Physician-Scientist Early Career Awardee and is a recipient of a 2006 Doris Duke Clinical Scientist Development Award. This work was supported by grants from the US National Institutes of Health (R01 CA129435 to M.L.F. and R01 CA109147 to G.A.C.), the Mayer Foundation (to M.L.F.), the H.L. Snyder Medical Foundation (to M.L.F.), the Dana-Farber/Harvard Cancer Center Prostate Cancer SPORE (National Cancer Institute Grant No. 5P50CA90381), the Prostate Cancer Foundation (to G.A.C. and to M.M.P.), the Whittier Foundation (to G.A.C.), the American Cancer Society Institutional Research Grant (IRG – 58-007-48 to L.J.) and the American Society of Clinical Oncology (to M.M.P.). We also acknowledge M.A. Brown for his support and guidance.

Author information

Author notes

    • Mark M Pomerantz
    •  & Nasim Ahmadiyeh

    These authors contributed equally to this work.

Affiliations

  1. Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.

    • Mark M Pomerantz
    • , Nasim Ahmadiyeh
    • , Paula Herman
    • , Michael P Verzi
    • , Christine A Beckwith
    • , Adam Hills
    • , Matt Davis
    • , Keluo Yao
    • , Sarah M Kehoe
    • , Jordi Barretina
    • , Adam Bass
    • , Ramesh Shivdasani
    •  & Matthew L Freedman
  2. Department of Surgery, Brigham and Women's Hospital, Boston, Massachusetts, USA.

    • Nasim Ahmadiyeh
  3. Department of Urology, Keck School of Medicine of USC, Los Angeles, California, USA.

    • Li Jia
    • , Chunli Yan
    •  & Gerhard A Coetzee
  4. Department of Biology and the Roy J. Carver Center for Genomics, University of Iowa, Iowa City, Iowa, USA.

    • Harshavardhan Doddapaneni
    •  & J Robert Manak
  5. Department of Pathology and Laboratory Medicine, University of Calgary, Alberta, Canada.

    • Jennifer A Chan
  6. Department of Preventive Medicine, Keck School of Medicine, Los Angeles, California, USA.

    • Heinz-Josef Lenz
    • , Christopher A Haiman
    •  & Brian E Henderson
  7. Institute for Genetic Medicine, Keck School of Medicine, Los Angeles, California, USA.

    • Baruch Frenkel
  8. Vall d'Hebron Institute of Oncology, Vall d'Hebron University Hospital, Catalonia, Spain.

    • Josep Tabernero
    •  & José Baselga
  9. Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.

    • Meredith M Regan
  10. The Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA.

    • Matthew L Freedman

Authors

  1. Search for Mark M Pomerantz in:

  2. Search for Nasim Ahmadiyeh in:

  3. Search for Li Jia in:

  4. Search for Paula Herman in:

  5. Search for Michael P Verzi in:

  6. Search for Harshavardhan Doddapaneni in:

  7. Search for Christine A Beckwith in:

  8. Search for Jennifer A Chan in:

  9. Search for Adam Hills in:

  10. Search for Matt Davis in:

  11. Search for Keluo Yao in:

  12. Search for Sarah M Kehoe in:

  13. Search for Heinz-Josef Lenz in:

  14. Search for Christopher A Haiman in:

  15. Search for Chunli Yan in:

  16. Search for Brian E Henderson in:

  17. Search for Baruch Frenkel in:

  18. Search for Jordi Barretina in:

  19. Search for Adam Bass in:

  20. Search for Josep Tabernero in:

  21. Search for José Baselga in:

  22. Search for Meredith M Regan in:

  23. Search for J Robert Manak in:

  24. Search for Ramesh Shivdasani in:

  25. Search for Gerhard A Coetzee in:

  26. Search for Matthew L Freedman in:

Contributions

M.M.P., N.A. and M.L.F. designed the study, analyzed all genetic and epigenetic data and wrote the manuscript. L.J., C.A.H., C.Y., B.E.H., B.F. and G.A.C. performed and analyzed ChIP and luciferase assays. M.M.P., N.A., P.H. and A.H. performed 3C experiments. M.P.V. and R.S. performed and analyzed ChIP experiments. H.D. and J.R.M. performed analysis of expression array. C.A.B. performed expression analysis of colon samples. J.A.C. analyzed colon samples and isolated nucleic acid. M.D., K.Y. and S.M.K. performed mass array assays. H.-J.L., J.Bar., A.B., J.T. and J.Bas. collected and supplied colon samples. M.M.R. contributed statistical analysis. M.L.F. conceived and directed the study.

Competing interests

Dr. Manak and his group generated the expression tiling array data while he was employed at Roche NimbleGen. Dr. Manak is currently employed at the University of Iowa and has no competing financial interests with Roche NimbleGen.

Corresponding author

Correspondence to Matthew L Freedman.

Supplementary information

PDF files

  1. 1.

    Supplementary Text and Figures

    Supplementary Tables 1 and 2, Supplementary Figures 1–6 and Supplementary Methods

About this article

Publication history

Received

Accepted

Published

DOI

https://doi.org/10.1038/ng.403

Further reading