A Polymorphic Enhancer near GREM1 Influences Bowel Cancer Risk through Differential CDX2 and TCF7L2 Binding

作者：Lewis Annabelle; Freeman Mills Luke; de la Calle Mustienes Elisa; Giraldez Perez Rosa Maria; Davis Hayley; Jaeger Emma; Becker Martin; Hubner Nina C; Nguyen Luan N; Zeron Medina Jorge; Bond Gareth; Stunnenberg Hendrik G; Carvajal Jaime J; Gomez Skarmeta Jose Luis; Leedham Simon; Tomlinson Ian^*

来源：Cell Reports, 2014, 8(4): 983-990.

DOI：10.1016/j.celrep.2014.07.020

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.

• 出版日期2014-8-21