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

نویسندگان

  • 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
چکیده

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.

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عنوان ژورنال:

دوره 8  شماره 

صفحات  -

تاریخ انتشار 2014