Journal
CELL REPORTS
Volume 8, Issue 4, Pages 983-990Publisher
CELL PRESS
DOI: 10.1016/j.celrep.2014.07.020
Keywords
-
Categories
Funding
- Cancer Research UK [A/16459]
- EU FP7 SYSCOL Consortium grant
- EU COST colorectal cancer initiative
- Spanish/FEDER government [BFU2010-14839, BFU2011-2292]
- Wellcome Trust [090532/Z/09/Z]
- Cancer Research UK [16459, 16581] Funding Source: researchfish
- Medical Research Council [MR/K000063/1, 1243081] Funding Source: researchfish
- MRC [MR/K000063/1] Funding Source: UKRI
Ask authors/readers for more resources
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 similar to 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.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available