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Cell Rep. 2014 Aug 21;8(4):983-90. doi: 10.1016/j.celrep.2014.07.020. Epub 2014 Aug 14.

A polymorphic enhancer near GREM1 influences bowel cancer risk through differential CDX2 and TCF7L2 binding.

Author information

1
Molecular and Population Genetics Laboratory, Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, UK.
2
Centro Andaluz de Biología del Desarrollo, CSIC-Universidad Pablo de Olavide-Junta de Andalucía, Carretera de Utrera Km1, 41013 Sevilla, Spain.
3
Max Planck Institute for Psycholinguistics, Wundtlaan 1, 6525 XD Nijmegen, the Netherlands.
4
Department of Molecular Biology, Radboud Institute for Molecular Life Science, Geert Grooteplein 26/28, 6525 GA Nijmegen, the Netherlands.
5
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.
6
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.

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.

PMID:
25131200
PMCID:
PMC4471812
DOI:
10.1016/j.celrep.2014.07.020
[Indexed for MEDLINE]
Free PMC Article

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