|Publication Type||Journal Article|
|Year of Publication||2013|
|Authors||Nan, H, Morikawa, T, Suuriniemi, M, Imamura, Y, Werner, L, Kuchiba, A, Yamauchi, M, Hunter, DJ, Kraft, P, Giovannucci, EL, Fuchs, CS, Ogino, S, Freedman, ML, Chan, AT|
|Journal||J Natl Cancer Inst|
|Date Published||2013 Dec 18|
|Keywords||Adult, Aged, Anti-Inflammatory Agents, Non-Steroidal, Anticarcinogenic Agents, Aspirin, beta Catenin, Case-Control Studies, Chromatin Immunoprecipitation, Chromosomes, Human, Pair 8, Colorectal Neoplasms, Drug Administration Schedule, Female, Follow-Up Studies, Genetic Predisposition to Disease, Humans, Logistic Models, Male, Middle Aged, Odds Ratio, Polymorphism, Single Nucleotide, Prospective Studies, Signal Transduction, Transcription Factor 7-Like 2 Protein, Wnt Proteins|
BACKGROUND: Regular aspirin use reduces the risk for colorectal cancer (CRC), possibly through inhibition of WNT/cadherin-associated protein β1 (CTNNB1 or β-catenin) signaling. The single nucleotide polymorphism (SNP) rs6983267 on chromosome 8q24 is a CRC susceptibility locus that affects binding activity of transcription factor 7 like-2 (TCF7L2) to CTNNB1, thereby altering expression of target oncogenes, including MYC.
METHODS: We evaluated regular aspirin use and CRC risk according to genotypes of SNP rs6983267 and CTNNB1 expression status in two prospective case-control studies (840 CRC case patients and 1686 age- and race-matched control subjects) nested within the Nurses' Health Study and the Health Professionals Follow-up Study. We estimated odds ratios (ORs) and 95% confidence intervals (CIs) using unconditional logistic regression models. All statistical tests were two-sided.
RESULTS: A lower risk of CRC was associated with regular aspirin use and the T allele of rs6983267. The effect of aspirin was confined to individuals with protective T allele of rs6983267 (additive matching factors-adjusted OR for T allele = 0.83; 95% CI = 0.74 to 0.94; P trend = .002; P interaction = .01). Additionally, the T allele of rs6983267 was associated with a reduced expression of MYC oncogene (P trend = .03). Moreover, among individuals with protective T allele, the effect of regular aspirin use was limited to those with positive nuclear CTNNB1 expression. In a functional analysis, in vitro treatment of LS174T cells (a cell line heterozygous for rs6983267) with aspirin was statistically significantly associated with higher G/T allelic ratio of TCF7L2 immunoprecipitated DNA (P = .03).
CONCLUSIONS: Our results support an influence of aspirin on WNT/CTNNB1 signaling and suggest that aspirin chemoprevention may be tailored according to rs6983267 genotype.
|Alternate Journal||J. Natl. Cancer Inst.|
|PubMed Central ID||PMC3866156|
|Grant List||R01 CA137178 / CA / NCI NIH HHS / United States |
R01 CA151993 / CA / NCI NIH HHS / United States
K24 DK098311 / DK / NIDDK NIH HHS / United States
P01 CA87969 / CA / NCI NIH HHS / United States
R01 CA169141 / CA / NCI NIH HHS / United States
P50 CA127003 / CA / NCI NIH HHS / United States