title: A polymorphic enhancer near GREM1 influences bowel cancer risk through differential CDX2 and TCF7L2 binding.
abstract: A rare germline duplication upstream of the bone morphogenetic protein antagonist GREM1 causes a Mendelian-dominant predisposition to colorectal cancer (CRC). The underlying disease mechanism is strong, ectopic GREM1 overexpression in the intestinal epithelium. Here, we confirm that a common GREM1 polymorphism, rs16969681, is also associated with CRC susceptibility, conferring ∼20% differential risk in the general population. We hypothesized the underlying cause to be moderate differences in GREM1 expression. We showed that rs16969681 lies in a region of active chromatin with allele- and tissue-specific enhancer activity. The CRC high-risk allele was associated with stronger gene expression, and higher Grem1 mRNA levels increased the intestinal tumor burden in Apc(Min) mice. The intestine-specific transcription factor CDX2 and Wnt effector TCF7L2 bound near rs16969681, with significantly higher affinity for the risk allele, and CDX2 overexpression in CDX2/GREM1-negative cells caused re-expression of GREM1. rs16969681 influences CRC risk through effects on Wnt-driven GREM1 expression in colorectal tumors.
authors.affiliation: Molecular and Population Genetics Laboratory, Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, UK.
authors.forename: Annabelle
authors.initials: A
authors.lastname: Lewis
authors.affiliation: Molecular and Population Genetics Laboratory, Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, UK.
authors.forename: Luke
authors.initials: L
authors.lastname: Freeman-Mills
authors.affiliation: Centro Andaluz de Biología del Desarrollo, CSIC-Universidad Pablo de Olavide-Junta de Andalucía, Carretera de Utrera Km1, 41013 Sevilla, Spain.
authors.forename: Elisa
authors.initials: E
authors.lastname: de la Calle-Mustienes
authors.affiliation: Centro Andaluz de Biología del Desarrollo, CSIC-Universidad Pablo de Olavide-Junta de Andalucía, Carretera de Utrera Km1, 41013 Sevilla, Spain.
authors.forename: Rosa María
authors.initials: RM
authors.lastname: Giráldez-Pérez
authors.affiliation: Molecular and Population Genetics Laboratory, Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, UK.
authors.forename: Hayley
authors.initials: H
authors.lastname: Davis
authors.affiliation: Molecular and Population Genetics Laboratory, Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, UK.
authors.forename: Emma
authors.initials: E
authors.lastname: Jaeger
authors.affiliation: Max Planck Institute for Psycholinguistics, Wundtlaan 1, 6525 XD Nijmegen, the Netherlands.
authors.forename: Martin
authors.initials: M
authors.lastname: Becker
authors.affiliation: Department of Molecular Biology, Radboud Institute for Molecular Life Science, Geert Grooteplein 26/28, 6525 GA Nijmegen, the Netherlands.
authors.forename: Nina C
authors.initials: NC
authors.lastname: Hubner
authors.affiliation: Department of Molecular Biology, Radboud Institute for Molecular Life Science, Geert Grooteplein 26/28, 6525 GA Nijmegen, the Netherlands.
authors.forename: Luan N
authors.initials: LN
authors.lastname: Nguyen
authors.affiliation: Ludwig Institute for Cancer Research, Ltd., Nuffield Department of Clinical Medicine, University of Oxford, Old Road Campus Research Building, Roosevelt Drive, Oxford OX3 7DQ, UK.
authors.forename: Jorge
authors.initials: J
authors.lastname: Zeron-Medina
authors.affiliation: Ludwig Institute for Cancer Research, Ltd., Nuffield Department of Clinical Medicine, University of Oxford, Old Road Campus Research Building, Roosevelt Drive, Oxford OX3 7DQ, UK.
authors.forename: Gareth
authors.initials: G
authors.lastname: Bond
authors.affiliation: Department of Molecular Biology, Radboud Institute for Molecular Life Science, Geert Grooteplein 26/28, 6525 GA Nijmegen, the Netherlands.
authors.forename: Hendrik G
authors.initials: HG
authors.lastname: Stunnenberg
authors.affiliation: Centro Andaluz de Biología del Desarrollo, CSIC-Universidad Pablo de Olavide-Junta de Andalucía, Carretera de Utrera Km1, 41013 Sevilla, Spain.
authors.forename: Jaime J
authors.initials: JJ
authors.lastname: Carvajal
authors.affiliation: Centro Andaluz de Biología del Desarrollo, CSIC-Universidad Pablo de Olavide-Junta de Andalucía, Carretera de Utrera Km1, 41013 Sevilla, Spain.
authors.forename: Jose Luis
authors.initials: JL
authors.lastname: Gomez-Skarmeta
authors.affiliation: Molecular and Population Genetics Laboratory, Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, UK.
authors.forename: Simon
authors.initials: S
authors.lastname: Leedham
authors.affiliation: Molecular and Population Genetics Laboratory, Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, UK. Electronic address: iant@well.ox.ac.uk.
authors.forename: Ian
authors.initials: I
authors.lastname: Tomlinson
mesh_terms: D000818:Animals; D001483:Base Sequence; D000071616:CDX2 Transcription Factor; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000235:genetics*; D004742:Enhancer Elements, Genetic; D015972:Gene Expression Regulation, Neoplastic; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D018398:Homeodomain Proteins / Q000378:metabolism*; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics*; D008822:Mice, Transgenic; D009928:Organ Specificity; D020641:Polymorphism, Single Nucleotide; D012306:Risk; D058118:Transcription Factor 7-Like 2 Protein / Q000378:metabolism*
chemical_list: D000071616:CDX2 Transcription Factor; C491270:CDX2 protein, human; C486399:GREM1 protein, human; D018398:Homeodomain Proteins; D036341:Intercellular Signaling Peptides and Proteins; C544894:TCF7L2 protein, human; D058118:Transcription Factor 7-Like 2 Protein