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The common colorectal cancer predisposition SNP rs6983267 at chromosome 8q24 confers potential to enhanced Wnt signaling

Nature Genetics volume 41, pages 885–890 (2009)Cite this article

Abstract

Homozygosity for the G allele of rs6983267 at 8q24 increases colorectal cancer (CRC) risk ∼1.5 fold. We report here that the risk allele G shows copy number increase during CRC development. Our computer algorithm, Enhancer Element Locator (EEL), identified an enhancer element that contains rs6983267. The element drove expression of a reporter gene in a pattern that is consistent with regulation by the key CRC pathway Wnt. rs6983267 affects a binding site for the Wnt-regulated transcription factor TCF4, with the risk allele G showing stronger binding in vitro and in vivo. Genome-wide ChIP assay revealed the element as the strongest TCF4 binding site within 1 Mb of MYC. An unambiguous correlation between rs6983267 genotype and MYC expression was not detected, and additional work is required to scrutinize all possible targets of the enhancer. Our work provides evidence that the common CRC predisposition associated with 8q24 arises from enhanced responsiveness to Wnt signaling.

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Figure 1: Copy number analysis in CRCs using SNP arrays.
Figure 2: rs6983267 maps to a TCF4 site at a conserved regulatory element.
Figure 3: TCF4 and β-catenin occupancy at MYC-335 in CRC cells.
Figure 4: Verification of the MYC-335 enhancer element in transgenic mouse embryos.

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Acknowledgements

This work was supported by the grants from Academy of Finland (Finnish Center of Excellence Program 2006-2011), the Finnish Cancer Society, the Sigrid Juselius Foundation, the European Commission (LSHG-CT-2004-512142) and by grants to S.T. (Ida Montin Foundation, Biomedicum Helsinki Foundation, Paulo Foundation, Mary and Georg C. Ehrnrooth Foundation and Maud Kuistila Foundation). The work of R.S.H. and I.T. is supported by Cancer Research UK. We thank A. Syvänen from the Uppsala University SNP Platform and O. Monni from the University of Helsinki for Illumina Genome-analyzer sequencing, G. Yochum for control primer sequences for TCF4, and S. Marttinen, K. Pylvänäinen, T. Lehtinen, S. Miettinen, M. Kuris, M. Aho and I. Svedberg for technical assistance. L. Peltonen (National Public Health Institute) and the Nordic Center of Excellence in Disease Genetics provided the Finnish control SNP data.

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Author notes

  1. Sakari Vanharanta & Kimmo Palin

    Present address: Present addresses: Cancer Biology and Genetics Program, Memorial Sloan-Kettering Cancer Center, New York, New York, USA (S.V.) and Wellcome Trust Sanger Institute, Hinxton, Cambridge, UK (K.P.).,

  2. Department of Pathology, HUSLAB and Haartman Institute, Helsinki University Central Hospital, Helsinki, Finland.

  3. lauri.aaltonen@helsinki.fi

Authors and Affiliations

  1. Department of Medical Genetics, Genome-Scale Biology Research Program, Biomedicum Helsinki, University of Helsinki, Helsinki, Finland

    Sari Tuupanen, Rainer Lehtonen, Sakari Vanharanta, Iina Niittymäki, Auli Karhu & Lauri A Aaltonen

  2. Institute of Biomedicine, Genome-Scale Biology Research Program, Biomedicum Helsinki, University of Helsinki, Helsinki, Finland

    Mikko Turunen, Outi Hallikas, Teemu Kivioja, Mikael Björklund, Gonghong Wei, Jian Yan & Jussi Taipale

  3. Department of Molecular Medicine, National Public Health Institute, University of Helsinki, Helsinki, Finland

    Mikko Turunen, Outi Hallikas, Mikael Björklund, Gonghong Wei, Jian Yan & Jussi Taipale

  4. Department of Computer Science, University of Helsinki, Helsinki, Finland

    Teemu Kivioja, Kimmo Palin & Esko Ukkonen

  5. Department of Surgery, Jyväskylä Central Hospital, Jyväskylä, Finland

    Jukka-Pekka Mecklin

  6. The Second Department of Surgery, Helsinki University Hospital, Helsinki, Finland

    Heikki Järvinen

  7. Genome-Scale Biology Research Program, University of Helsinki, Helsinki, Finland

    Ari Ristimäki

  8. Department of Pathology, University of Oulu and Oulu University Hospital, Oulu, Finland

    Ari Ristimäki

  9. Section of Cancer Genetics, Institute of Cancer Research, Sutton, Surrey, UK

    Mariachiara Di-Bernardo & Richard S Houlston

  10. Wellcome Trust Centre for Human Genetics, Roosevelt Drive, Headington, Oxford, UK

    Phil East, Luis Carvajal-Carmona & Ian Tomlinson

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Contributions

The study was designed and financial support was obtained by L.A.A. and J.T. The manuscript was drafted by L.A.A., J.T. and S.T. Wet-lab experiments were performed by S.T., M.T., O.H., M.B., G.W., J.Y. and I.N. M.D.-B., I.T. and R.S.H. provided the imputed SNP data. J.-P.M. and H.J. provided the Finnish CRC specimens, A.R. contributed to histopathological evaluation of materials. R.L., S.V., T.K., P.E., L.C.-C., K.P. and A.K. performed the computational and statistical analyses. K.P., E.U. and S.T. performed the EEL analyses.

Corresponding authors

Correspondence to Jussi Taipale or Lauri A Aaltonen.

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Tuupanen, S., Turunen, M., Lehtonen, R. et al. The common colorectal cancer predisposition SNP rs6983267 at chromosome 8q24 confers potential to enhanced Wnt signaling. Nat Genet 41, 885–890 (2009). https://doi.org/10.1038/ng.406

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