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

Annabelle Lewis; Luke Freeman-Mills; Elisa de la Calle-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

doi:10.1016/j.celrep.2014.07.020

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

Annabelle Lewis, Luke Freeman-Mills, Elisa de la Calle-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

Cancer and Genomic Sciences

Research output: Contribution to journal › Article › peer-review

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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.

Original language	English
Pages (from-to)	983-990
Number of pages	8
Journal	Cell Reports
Volume	8
Issue number	4
Early online date	14 Aug 2014
DOIs	https://doi.org/10.1016/j.celrep.2014.07.020
Publication status	Published - 21 Aug 2014

Keywords

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

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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Lewis, A., Freeman-Mills, L., de la Calle-Mustienes, E., Giráldez-Pérez, R. M., Davis, H., Jaeger, E., Becker, M., Hubner, N. C., Nguyen, L. N., Zeron-Medina, J., Bond, G., Stunnenberg, H. G., Carvajal, J. J., Gomez-Skarmeta, J. L., Leedham, S., & Tomlinson, I. (2014). A polymorphic enhancer near GREM1 influences bowel cancer risk through differential CDX2 and TCF7L2 binding. Cell Reports, 8(4), 983-990. Advance online publication. https://doi.org/10.1016/j.celrep.2014.07.020

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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 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.",

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

author = "Annabelle Lewis and Luke Freeman-Mills and {de la Calle-Mustienes}, Elisa and Gir{\'a}ldez-P{\'e}rez, {Rosa Mar{\'i}a} and Hayley Davis and Emma Jaeger and Martin Becker and Hubner, {Nina C} and Nguyen, {Luan N} and Jorge Zeron-Medina and Gareth Bond and Stunnenberg, {Hendrik G} and Carvajal, {Jaime J} and Gomez-Skarmeta, {Jose Luis} and Simon Leedham and Ian Tomlinson",

year = "2014",

month = aug,

day = "21",

doi = "10.1016/j.celrep.2014.07.020",

language = "English",

volume = "8",

pages = "983--990",

journal = "Cell Reports",

issn = "2211-1247",

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Lewis, A, Freeman-Mills, L, de la Calle-Mustienes, E, Giráldez-Pérez, RM, Davis, H, Jaeger, E, Becker, M, Hubner, NC, Nguyen, LN, Zeron-Medina, J, Bond, G, Stunnenberg, HG, Carvajal, JJ, Gomez-Skarmeta, JL, Leedham, S & Tomlinson, I 2014, 'A polymorphic enhancer near GREM1 influences bowel cancer risk through differential CDX2 and TCF7L2 binding', Cell Reports, vol. 8, no. 4, pp. 983-990. https://doi.org/10.1016/j.celrep.2014.07.020

TY - JOUR

T1 - A polymorphic enhancer near GREM1 influences bowel cancer risk through differential CDX2 and TCF7L2 binding

AU - Lewis, Annabelle

AU - Freeman-Mills, Luke

AU - de la Calle-Mustienes, Elisa

AU - Giráldez-Pérez, Rosa María

AU - Davis, Hayley

AU - Jaeger, Emma

AU - Becker, Martin

AU - Hubner, Nina C

AU - Nguyen, Luan N

AU - Zeron-Medina, Jorge

AU - Bond, Gareth

AU - Stunnenberg, Hendrik G

AU - Carvajal, Jaime J

AU - Gomez-Skarmeta, Jose Luis

AU - Leedham, Simon

AU - Tomlinson, Ian

PY - 2014/8/21

Y1 - 2014/8/21

N2 - 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 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.

AB - 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 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.

KW - Animals

KW - Base Sequence

KW - CDX2 Transcription Factor

KW - Cell Line, Tumor

KW - Colonic Neoplasms/genetics

KW - Enhancer Elements, Genetic

KW - Gene Expression Regulation, Neoplastic

KW - Genetic Association Studies

KW - Genetic Predisposition to Disease

KW - Homeodomain Proteins/metabolism

KW - Humans

KW - Intercellular Signaling Peptides and Proteins/genetics

KW - Mice, Transgenic

KW - Organ Specificity

KW - Polymorphism, Single Nucleotide

KW - Risk

KW - Transcription Factor 7-Like 2 Protein/metabolism

U2 - 10.1016/j.celrep.2014.07.020

DO - 10.1016/j.celrep.2014.07.020

M3 - Article

C2 - 25131200

SN - 2211-1247

VL - 8

SP - 983

EP - 990

JO - Cell Reports

JF - Cell Reports

IS - 4

ER -

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

Abstract

Keywords

UN SDGs

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