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The 8q24 cancer risk variant rs6983267 shows long-range interaction with MYC in colorectal cancer

Nature Genetics 41, 882–884 (2009) | Download Citation

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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.

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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

    • 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

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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.

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

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DOI

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

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