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Genetic Variation in the TGF-beta Signaling Pathway and Colon and Rectal Cancer Risk

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AMER ASSOC CANCER RESEARCH
DOI: 10.1158/1055-9965.EPI-10-0843

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  1. NCI [CA48998, CA61757, N01-PC-67000]
  2. State of Utah Department of Health
  3. Northern California Cancer Registry
  4. Sacramento Tumor Registry
  5. DIVISION OF CANCER CONTROL &POPULATION SCIENCE [N01PC067000] Funding Source: NIH RePORTER
  6. NATIONAL CANCER INSTITUTE [U01CA048998, R01CA061757, R01CA048998] Funding Source: NIH RePORTER

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Background: The TGF-beta signaling pathway is an essential regulator of many cellular process involved in carcinogenesis. Smad proteins are central to the function of TGF-beta signaling. In this study, we evaluated genetic variation in TGF beta 1, TGF beta R1, Smad1, Smad2, Smad3, and Smad4 and risk of colon and rectal cancer. Methods: Data are from a large case-control study of colon (n = 1,444 cases, 1,841 controls) and rectal (n 754 cases, 856 controls) cancer participants with DNA. Results: Both TGF beta 1 rs1800469 and rs4803455 were associated with colon cancer [odds ratio (OR) = 0.65 and 1.43, 95% CI = 0.51-0.84 and 1.18-1.73, respectively) but not rectal cancer. Likewise, 1 of 3 tagSNPs for TGF beta R1, 2 of the 4 tagSNPs for Smad2, and 4 of 37 Smad3 tagSNPs were associated with colon cancer. Fewer significant associations were observed for rectal cancer, with only 1 tagSNP in Smad2 and 3 tagSNP in Smad3 having 95% CIs excluding 1.0. Several Smad3 tagSNPs were only associated with CpG island methylator phenotype. We observed several statistically significant interactions between genetic variation in the TGF-beta signaling pathway and NF kappa B1, further illustrating its involvement in proposed mechanisms. In addition, we observed statistically significant interaction between TGF beta 1, TGF beta R1, and Smad3 and cigarette smoking, aspirin use, and estrogen status for both colon and rectal cancers. Variation in TGF beta 1, TGF beta R1, and Smad3 seemed to influence survival after diagnosis of colon and rectal cancer. Conclusions: These findings provide further support for genetic variation in the TGF-beta signaling pathway and risk of developing both colon and rectal cancers. Impact: Insight into biological pathways is provided. Cancer Epidemiol Biomarkers Prev; 20(1); 57-69. (C) 2011 AACR.

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