Multiple functional risk variants in a SMAD7 enhancer implicate a colorectal cancer risk haplotype.
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.
Department of Preventive Medicine, University of Southern California, Los Angeles, California, United States of America.
Barbara K
BK
Fortini
Department of Preventive Medicine, University of Southern California, Los Angeles, California, United States of America.
Stephanie
S
Tring
Department of Preventive Medicine, University of Southern California, Los Angeles, California, United States of America.
Sarah J
SJ
Plummer
Department of Preventive Medicine, University of Southern California, Los Angeles, California, United States of America.
Christopher K
CK
Edlund
Cancer Prevention and Control Program, Catalan Institute of Oncology, CIBERESP and University of Barcelona, Hospitalet de Llobregat, Barcelona, Spain.
Victor
V
Moreno
Department of Gastroenterology, Hepatology and Nutrition, University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America.
Robert S
RS
Bresalier
Department of Community and Family Medicine, Geisel School of Medicine at Dartmouth, Lebanon, New Hampshire, United States of America.
Elizabeth L
EL
Barry
Division of Environmental Health Sciences, University of Minnesota School of Public Health, Minneapolis, Minnesota, United States of America.
Timothy R
TR
Church
Department of Preventive Medicine, University of Southern California, Los Angeles, California, United States of America.
Jane C
JC
Figueiredo
Department of Preventive Medicine, University of Southern California, Los Angeles, California, United States of America.
Graham
G
Casey
D019485:Bone Morphogenetic Proteins / Q000378:metabolism*; D045744:Cell Line, Tumor; D002887:Chromosomes, Human, Pair 18 / Q000235:genetics; D015179:Colorectal Neoplasms / Q000235:genetics*; D004742:Enhancer Elements, Genetic; D014644:Genetic Variation; D045325:HCT116 Cells; D057809:HEK293 Cells; D006801:Humans; D015810:Linkage Disequilibrium; D020641:Polymorphism, Single Nucleotide; D015398:Signal Transduction; D051906:Smad7 Protein / Q000235:genetics*; D016212:Transforming Growth Factor beta / Q000378:metabolism
D019485:Bone Morphogenetic Proteins; C497806:SMAD7 protein, human; D051906:Smad7 Protein; D016212:Transforming Growth Factor beta