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 - delaCalle-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
N1 - Funding Information:
Funding was provided from Cancer Research UK grant A/16459, an EU FP7 SYSCOL Consortium grant, and the EU COST colorectal cancer initiative. Core funding to the Wellcome Trust Centre for Human Genetics was provided from the Wellcome Trust (090532/Z/09/Z). J.L.G.-S. and J.J.C. were supported by the Spanish/FEDER government grants BFU2010-14839 and BFU2011-2292. We thank R. Almeida for the CMV-CDX2 overexpression plasmid, E. Canalis for Grem1 mice, and the High-Throughput Genomics Group at the Wellcome Trust Centre for Human Genetics for Sequenom data.
PY - 2014/8/21
Y1 - 2014/8/21
N2 - 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.
AB - 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.
UR - https://www.scopus.com/pages/publications/84908356322
U2 - 10.1016/j.celrep.2014.07.020
DO - 10.1016/j.celrep.2014.07.020
M3 - Article
C2 - 25131200
AN - SCOPUS:84908356322
SN - 2211-1247
VL - 8
SP - 983
EP - 990
JO - Cell reports
JF - Cell reports
IS - 4
ER -