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J Natl Cancer Inst DOI:10.1093/jnci/djt331

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

Publication TypeJournal Article
Year of Publication2013
AuthorsNan, 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
JournalJ Natl Cancer Inst
Volume105
Issue24
Pages1852-61
Date Published2013 Dec 18
ISSN1460-2105
KeywordsAdult, 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
Abstract

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.

URLhttp://jnci.oxfordjournals.org/cgi/pmidlookup?view=long&pmid=24317174
DOI10.1093/jnci/djt331
Pubmed

http://www.ncbi.nlm.nih.gov/pubmed/24317174?dopt=Abstract

Alternate JournalJ. Natl. Cancer Inst.
PubMed ID24317174
PubMed Central IDPMC3866156
Grant ListR01 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