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The 14q22.2 colorectal cancer variant rs4444235 shows cis-acting regulation of BMP4

Oncogene volume 31, pages 3777–3784 (2012)Cite this article

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Abstract

Common genetic variation at human 14q22.2 tagged by rs4444235 is significantly associated with colorectal cancer (CRC) risk. Re-sequencing was used to comprehensively annotate the 17kb region of strong linkage disequilibrium encompassing rs4444235. Through bioinformatic analyses using H3K4Me1, H3K4Me3, and DNase-I hypersensitivity chromatin signatures and evolutionary conservation we identified seven candidate disease-causing single-nucleotide polymorphisms mapping to six regions within the 17-kb region predicted to have regulatory potential. Reporter gene studies of these regions demonstrated that the element to which rs4444235 maps acts as an allele-specific transcriptional enhancer. Allele-specific expression studies in CRC cell lines heterozygous for rs4444235 showed significantly increased expression of bone morphogenetic protein-4 (BMP4) associated with the risk allele (P<0.001). These data provide evidence for a functional basis for the non-coding risk variant rs4444235 at 14q22.2 and emphasizes the importance of genetic variation in the BMP pathway genes as determinants of CRC risk.

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Acknowledgements

We acknowledge the National Health Service (NHS) funding to the National Institute for Health Research (NIHR) Biomedical Research Centre. Finally, we are grateful to all patients and individuals for participation. Cancer Research UK (C1298/A8362 supported by the Bobby Moore Fund) provided principal funding for the study. JLG-S acknowledges grants from the Spanish Ministry of Education and Science (BFU2010-14839 and CSD2007-00008) and Junta de Andalucía (CVI-3488). SJL is in receipt of a PhD studentship from Cancer Research UK. The research leading to these results has received funding from the European Union Seventh Framework Programme (FP7/207-2013) under grant no. 258236, FP7 collaborative project SYSCOL.

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Authors and Affiliations

  1. Section of Cancer Genetics, Institute of Cancer Research, Surrey, UK

    S J Lubbe, A M Pittman, B Olver, A Lloyd, J Vijayakrishnan, S Dobbins, P Broderick & R S Houlston

  2. Centro Andaluz de Biología del Desarrollo, CSIC-UPO, Carretera de Utrera Km1, Seville, Spain

    S Naranjo & J L Gómez-Skarmeta

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  1. S J Lubbe
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Correspondence to R S Houlston.

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Lubbe, S., Pittman, A., Olver, B. et al. The 14q22.2 colorectal cancer variant rs4444235 shows cis-acting regulation of BMP4. Oncogene 31, 3777–3784 (2012). https://doi.org/10.1038/onc.2011.564

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