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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.

Original publication

DOI

10.1016/j.celrep.2014.07.020

Type

Journal article

Journal

Cell Rep

Publication Date

21/08/2014

Volume

8

Pages

983 - 990

Keywords

Animals, Base Sequence, CDX2 Transcription Factor, Cell Line, Tumor, Colonic Neoplasms, Enhancer Elements, Genetic, Gene Expression Regulation, Neoplastic, Genetic Association Studies, Genetic Predisposition to Disease, Homeodomain Proteins, Humans, Intercellular Signaling Peptides and Proteins, Mice, Transgenic, Organ Specificity, Polymorphism, Single Nucleotide, Risk, Transcription Factor 7-Like 2 Protein