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

Annabelle Lewis, Luke Freeman-Mills, Elisa delaCalle-Mustienes, Rosa María Giráldez-Pérez, Hayley Davis, Emma Jaeger, Martin Becker, Nina C. Hubner, Luan N. Nguyen, Jorge Zeron-Medina, Gareth Bond, Hendrik G. Stunnenberg, Jaime J. Carvajal, Jose Luis Gomez-Skarmeta, Simon Leedham, Ian Tomlinson

Research output: Contribution to journalArticlepeer-review

41 Citations (Scopus)

Abstract

A rare germline duplication upstream of the bone morphogenetic protein antagonist GREM1 causes aMendelian-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 inGREM1 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 ApcMin 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 languageEnglish
Pages (from-to)983-990
Number of pages8
JournalCell Reports
Volume8
Issue number4
DOIs
Publication statusPublished - 21 Aug 2014
Externally publishedYes

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