Genetic variation in the TGF-β signaling pathway and colon and rectal cancer risk.
BACKGROUND
The TGF-β signaling pathway is an essential regulator of many cellular process involved in carcinogenesis. Smad proteins are central to the function of TGF-β signaling. In this study, we evaluated genetic variation in TGFβ1, TGFβR1, 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 TGFβ1 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 TGFβR1, 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-β signaling pathway and NFκB1, further illustrating its involvement in proposed mechanisms. In addition, we observed statistically significant interaction between TGFβ1, TGFβR1, and Smad3 and cigarette smoking, aspirin use, and estrogen status for both colon and rectal cancers. Variation in TGFβ1, TGFβR1, 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-β signaling pathway and risk of developing both colon and rectal cancers.


CONCLUSIONS
Insight into biological pathways is provided.
Department of Internal Medicine, University of Utah Health Sciences Center, 295 Chipeta Way, Salt Lake City, Utah 84108, USA. marty.slattery@hsc.utah.edu
Martha L
ML
Slattery
Jennifer S
JS
Herrick
Abbie
A
Lundgreen
Roger K
RK
Wolff
D000328:Adult; D000368:Aged; D016022:Case-Control Studies; D048708:Cell Growth Processes / Q000235:genetics; D003110:Colonic Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D005260:Female; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D006801:Humans; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D012004:Rectal Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D015398:Signal Transduction; D051785:Smad Proteins / Q000235:genetics / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000235:genetics* / Q000378:metabolism
D051785:Smad Proteins; D016212:Transforming Growth Factor beta