The non-coding variant rs1800734 enhances DCLK3 expression through long-range interaction and promotes colorectal cancer progression

Ning Qing Liu (), Menno ter Huurne, Luan N. Nguyen, Tianran Peng, Shuang-Yin Wang, James B. Studd, Onkar Joshi, Halit Ongen, Jesper B Bramsen, Jian Yan, Claus L. Andersen, Jussi Taipale, Emmanouil T. Dermitzakis, Richard S. Houlston, Nina C. Hubner and Hendrik G. Stunnenberg ()
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Ning Qing Liu: Faculty of Science, Radboud University
Menno ter Huurne: Faculty of Science, Radboud University
Luan N. Nguyen: Faculty of Science, Radboud University
Tianran Peng: Faculty of Science, Radboud University
Shuang-Yin Wang: Faculty of Science, Radboud University
James B. Studd: Institute of Cancer Research
Onkar Joshi: Faculty of Science, Radboud University
Halit Ongen: University of Geneva Medical School
Jesper B Bramsen: Aarhus University Hospital
Jian Yan: Karolinska Institutet
Claus L. Andersen: Aarhus University Hospital
Jussi Taipale: Karolinska Institutet
Emmanouil T. Dermitzakis: University of Geneva Medical School
Richard S. Houlston: Institute of Cancer Research
Nina C. Hubner: Faculty of Science, Radboud University
Hendrik G. Stunnenberg: Faculty of Science, Radboud University

Nature Communications, 2017, vol. 8, issue 1, 1-10

Abstract: Abstract Genome-wide association studies have identified a great number of non-coding risk variants for colorectal cancer (CRC). To date, the majority of these variants have not been functionally studied. Identification of allele-specific transcription factor (TF) binding is of great importance to understand regulatory consequences of such variants. A recently developed proteome-wide analysis of disease-associated SNPs (PWAS) enables identification of TF-DNA interactions in an unbiased manner. Here we perform a large-scale PWAS study to comprehensively characterize TF-binding landscape that is associated with CRC, which identifies 731 allele-specific TF binding at 116 CRC risk loci. This screen identifies the A-allele of rs1800734 within the promoter region of MLH1 as perturbing the binding of TFAP4 and consequently increasing DCLK3 expression through a long-range interaction, which promotes cancer malignancy through enhancing expression of the genes related to epithelial-to-mesenchymal transition.

Date: 2017
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DOI: 10.1038/ncomms14418

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