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PLoS One. 2014 Nov 6;9(11):e111914. doi: 10.1371/journal.pone.0111914. eCollection 2014.

Multiple functional risk variants in a SMAD7 enhancer implicate a colorectal cancer risk haplotype.

Author information

  • 1Department of Preventive Medicine, University of Southern California, Los Angeles, California, United States of America.
  • 2Cancer Prevention and Control Program, Catalan Institute of Oncology, CIBERESP and University of Barcelona, Hospitalet de Llobregat, Barcelona, Spain.
  • 3Department of Gastroenterology, Hepatology and Nutrition, University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America.
  • 4Department of Community and Family Medicine, Geisel School of Medicine at Dartmouth, Lebanon, New Hampshire, United States of America.
  • 5Division of Environmental Health Sciences, University of Minnesota School of Public Health, Minneapolis, Minnesota, United States of America.

Abstract

Genome-wide association studies (GWAS) of colorectal cancer (CRC) have led to the identification of a number of common variants associated with modest risk. Several risk variants map within the vicinity of TGFβ/BMP signaling pathway genes, including rs4939827 within an intron of SMAD7 at 18q21.1. A previous study implicated a novel SNP (novel 1 or rs58920878) as a functional variant within an enhancer element in SMAD7 intron 4. In this study, we show that four SNPs including novel 1 (rs6507874, rs6507875, rs8085824, and rs58920878) in linkage disequilibrium (LD) with the index SNP rs4939827 demonstrate allele-specific enhancer effects in a large, multi-component enhancer of SMAD7. All four SNPs demonstrate allele-specific protein binding to nuclear extracts of CRC cell lines. Furthermore, some of the risk-associated alleles correlate with increased expression of SMAD7 in normal colon tissues. Finally, we show that the enhancer is responsive to BMP4 stimulation. Taken together, we propose that the associated CRC risk at 18q21.1 is due to four functional variants that regulate SMAD7 expression and potentially perturb a BMP negative feedback loop in TGFβ/BMP signaling pathways.

PMID:
25375357
[PubMed - indexed for MEDLINE]
PMCID:
PMC4223076
Free PMC Article
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