Aspirin use, 8q24 single nucleotide polymorphism rs6983267, and colorectal cancer according to CTNNB1 alterations

J Natl Cancer Inst. 2013 Dec 18;105(24):1852-61. doi: 10.1093/jnci/djt331. Epub 2013 Dec 7.


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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adult
  • Aged
  • Anti-Inflammatory Agents, Non-Steroidal / administration & dosage
  • Anticarcinogenic Agents / administration & dosage*
  • Aspirin / administration & dosage*
  • Case-Control Studies
  • Chromatin Immunoprecipitation
  • Chromosomes, Human, Pair 8*
  • Colorectal Neoplasms / genetics*
  • Colorectal Neoplasms / prevention & control*
  • 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 / metabolism
  • Wnt Proteins / metabolism
  • beta Catenin / genetics
  • beta Catenin / metabolism*


  • Anti-Inflammatory Agents, Non-Steroidal
  • Anticarcinogenic Agents
  • CTNNB1 protein, human
  • TCF7L2 protein, human
  • Transcription Factor 7-Like 2 Protein
  • Wnt Proteins
  • beta Catenin
  • Aspirin