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

Nature Genetics volume 41, pages 882–884 (2009)Cite this article

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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Figure 1: Enhancer activity at the CRC risk locus and allele-specific differences in enhancer activity and TCF7L2 binding.
Figure 2: Long-range physical interaction of the CRC risk variant rs6983267 with MYC in CRC cell lines.

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Gene Expression Omnibus

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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.

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Author notes

  1. Mark M Pomerantz and Nasim Ahmadiyeh: These authors contributed equally to this work.

Authors and 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. Mark M Pomerantz
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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.

Corresponding author

Correspondence to Matthew L Freedman.

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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.

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Supplementary Tables 1 and 2, Supplementary Figures 1–6 and Supplementary Methods (PDF 578 kb)

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Pomerantz, M., Ahmadiyeh, N., Jia, L. et al. The 8q24 cancer risk variant rs6983267 shows long-range interaction with MYC in colorectal cancer. Nat Genet 41, 882–884 (2009). https://doi.org/10.1038/ng.403

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