Bríd M Ryan1, Roger K Wolff2, Nicola Valeri3, Mohammed Khan1, Dillon Robinson1, Alessio Paone4, Elise D Bowman1, Abbie Lundgreen2, Bette Caan5, John Potter6, Derek Brown1, Carlo Croce4, Martha L Slattery2, Curtis C Harris7. 1. Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA. 2. Department of Internal Medicine, University of Utah, Salt Lake City, UT 84132, USA. 3. Division of Molecular Pathology, The Institute of Cancer Research, 15 Cotswold Road, Belmont, Sutton Surrey SM2 5NG, UK. 4. Department of Molecular Virology, Immunology and Medical Genetics, Comprehensive Cancer Center, Ohio State University, Columbus, OH 43210, USA. 5. Department of Research, Kaiser Permanente Medical Research Program, 2000 Broadway, Oakland, CA 94612, USA. 6. Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA; Centre for Public Health Research, Massey University, Wellington, New Zealand; Department of Epidemiology, University of Washington, Seattle, WA 98109, USA. 7. Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA. Electronic address: Curtis_Harris@nih.gov.
Abstract
BACKGROUND AND AIMS: Patients with inflammatory bowel disease (IBD) have a higher risk of developing colorectal cancer than the general population. Genome-wide association studies have identified and replicated several loci associated with risk of IBD; however, it is currently unknown whether these loci are also associated with colon cancer risk. METHODS: We selected 15 validated SNPs associated with risk of either Crohn's disease, ulcerative colitis, or both in previous GWAS and tested whether these loci were also associated with colon cancer risk in a two-stage study design. RESULTS: We found that rs744166 in STAT3 was associated with colon cancer risk in two studies; however, the direction of the observation was reversed in TP53 mutant tumors possibly due to a nullification of the effect by mutant p53. The SNP, which lies within intron 1 of the STAT3 gene, was associated with lower expression of STAT3 mRNA in TP53 wild-type, but not mutant, tumors. CONCLUSIONS: These data suggest that the STAT3 locus is associated with both IBD and cancer. Further understanding the function of this variant in relation to TP53 could possibly explain the role of this gene in autoimmunity and cancer. Furthermore, an analysis of this locus, specifically in a population with IBD, could help to resolve the relationship between this SNP and cancer. Published by Elsevier Ltd.
BACKGROUND AND AIMS: Patients with inflammatory bowel disease (IBD) have a higher risk of developing colorectal cancer than the general population. Genome-wide association studies have identified and replicated several loci associated with risk of IBD; however, it is currently unknown whether these loci are also associated with colon cancer risk. METHODS: We selected 15 validated SNPs associated with risk of either Crohn's disease, ulcerative colitis, or both in previous GWAS and tested whether these loci were also associated with colon cancer risk in a two-stage study design. RESULTS: We found that rs744166 in STAT3 was associated with colon cancer risk in two studies; however, the direction of the observation was reversed in TP53 mutant tumors possibly due to a nullification of the effect by mutant p53. The SNP, which lies within intron 1 of the STAT3 gene, was associated with lower expression of STAT3 mRNA in TP53 wild-type, but not mutant, tumors. CONCLUSIONS: These data suggest that the STAT3 locus is associated with both IBD and cancer. Further understanding the function of this variant in relation to TP53 could possibly explain the role of this gene in autoimmunity and cancer. Furthermore, an analysis of this locus, specifically in a population with IBD, could help to resolve the relationship between this SNP and cancer. Published by Elsevier Ltd.
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