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Association of aspirin and NSAID use with risk of colorectal cancer according to genetic variants.

ABSTRACT: Use of aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs) is associated with lower risk of colorectal cancer.To identify common genetic markers that may confer differential benefit from aspirin or NSAID chemoprevention, we tested gene?×?environment interactions between regular use of aspirin and/or NSAIDs and single-nucleotide polymorphisms (SNPs) in relation to risk of colorectal cancer.Case-control study using data from 5 case-control and 5 cohort studies initiated between 1976 and 2003 across the United States, Canada, Australia, and Germany and including colorectal cancer cases (n=8634) and matched controls (n=8553) ascertained between 1976 and 2011. Participants were all of European descent.Genome-wide SNP data and information on regular use of aspirin and/or NSAIDs and other risk factors.Colorectal cancer.Regular use of aspirin and/or NSAIDs was associated with lower risk of colorectal cancer (prevalence, 28% vs 38%; odds ratio [OR], 0.69 [95% CI, 0.64-0.74]; P?=?6.2?×?10(-28)) compared with nonregular use. In the conventional logistic regression analysis, the SNP rs2965667 at chromosome 12p12.3 near the MGST1 gene showed a genome-wide significant interaction with aspirin and/or NSAID use (P?=?4.6?×?10(-9) for interaction). Aspirin and/or NSAID use was associated with a lower risk of colorectal cancer among individuals with rs2965667-TT genotype (prevalence, 28% vs 38%; OR, 0.66 [95% CI, 0.61-0.70]; P?=?7.7?×?10(-33)) but with a higher risk among those with rare (4%) TA or AA genotypes (prevalence, 35% vs 29%; OR, 1.89 [95% CI, 1.27-2.81]; P?=?.002). In case-only interaction analysis, the SNP rs16973225 at chromosome 15q25.2 near the IL16 gene showed a genome-wide significant interaction with use of aspirin and/or NSAIDs (P?=?8.2?×?10(-9) for interaction). Regular use was associated with a lower risk of colorectal cancer among individuals with rs16973225-AA genotype (prevalence, 28% vs 38%; OR, 0.66 [95% CI, 0.62-0.71]; P?=?1.9?×?10(-30)) but was not associated with risk of colorectal cancer among those with less common (9%) AC or CC genotypes (prevalence, 36% vs 39%; OR, 0.97 [95% CI, 0.78-1.20]; P?=?.76).In this genome-wide investigation of gene?×?environment interactions, use of aspirin and/or NSAIDs was associated with lower risk of colorectal cancer, and this association differed according to genetic variation at 2 SNPs at chromosomes 12 and 15. Validation of these findings in additional populations may facilitate targeted colorectal cancer prevention strategies.

SUBMITTER: Nan H

PROVIDER: S-EPMC4382867 | biostudies-literature | 2015 Mar

REPOSITORIES: biostudies-literature

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Association of aspirin and NSAID use with risk of colorectal cancer according to genetic variants.

Nan Hongmei H Hutter Carolyn M CM Lin Yi Y Jacobs Eric J EJ Ulrich Cornelia M CM White Emily E Baron John A JA Berndt Sonja I SI Brenner Hermann H Butterbach Katja K Caan Bette J BJ Campbell Peter T PT Carlson Christopher S CS Casey Graham G Chang-Claude Jenny J Chanock Stephen J SJ Cotterchio Michelle M Duggan David D Figueiredo Jane C JC Fuchs Charles S CS Giovannucci Edward L EL Gong Jian J Haile Robert W RW Harrison Tabitha A TA Hayes Richard B RB Hoffmeister Michael M Hopper John L JL Hudson Thomas J TJ Jenkins Mark A MA Jiao Shuo S Lindor Noralane M NM Lemire Mathieu M Le Marchand Loic L Newcomb Polly A PA Ogino Shuji S Pflugeisen Bethann M BM Potter John D JD Qu Conghui C Rosse Stephanie A SA Rudolph Anja A Schoen Robert E RE Schumacher Fredrick R FR Seminara Daniela D Slattery Martha L ML Thibodeau Stephen N SN Thomas Fridtjof F Thornquist Mark M Warnick Greg S GS Zanke Brent W BW Gauderman W James WJ Peters Ulrike U Hsu Li L Chan Andrew T AT

JAMA 20150301 11

<h4>Importance</h4>Use of aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs) is associated with lower risk of colorectal cancer.<h4>Objective</h4>To identify common genetic markers that may confer differential benefit from aspirin or NSAID chemoprevention, we tested gene × environment interactions between regular use of aspirin and/or NSAIDs and single-nucleotide polymorphisms (SNPs) in relation to risk of colorectal cancer.<h4>Design, setting, and participants</h4>Case-control stud ...[more]

PMID: 25781442

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Project description:ImportanceAspirin use reduces the risk of colorectal carcinoma. Experimental evidence implicates a role of RAF kinases in up-regulation of prostaglandin-endoperoxide synthase 2 (PTGS2, cyclooxygenase 2), suggesting that BRAF-mutant colonic cells might be less sensitive to the antitumor effects of aspirin than BRAF-wild-type neoplastic cells.ObjectiveTo examine whether the association of aspirin intake with colorectal cancer risk differs according to status of tumor BRAF oncogene mutation.Design and settingWe collected biennial questionnaire data on aspirin use and followed up participants in the Nurses' Health Study (from 1980) and the Health Professionals Follow-up Study (from 1986) until July 1, 2006, for cancer incidence and until January 1, 2012, for cancer mortality. Duplication-method Cox proportional cause-specific hazards regression for competing risks data was used to compute hazard ratios (HRs) for colorectal carcinoma incidence according to BRAF mutation status.Main outcomes and measuresIncidence of colorectal cancer cases according to tumor BRAF mutation status.ResultsAmong 127,865 individuals, with 3,165,985 person-years of follow-up, we identified 1226 incident rectal and colon cancers with available molecular data. Compared with nonuse, regular aspirin use was associated with lower BRAF-wild-type cancer risk (multivariable HR, 0.73; 95% CI, 0.64 to 0.83; age-adjusted incidence rate difference [RD], -9.7; 95% CI, -12.6 to -6.7 per 100,000 person-years). This association was observed irrespective of status of tumor PTGS2 expression or PIK3CA or KRAS mutation. In contrast, regular aspirin use was not associated with a lower risk of BRAF-mutated cancer (multivariable HR, 1.03; 95% CI, 0.76 to 1.38; age-adjusted, incidence RD, 0.7; 95% CI, -0.3 to 1.7 per 100,000 person-years: P for heterogeneity = .037, between BRAF-wild-type vs BRAF-mutated cancer risks). Compared with no aspirin use, aspirin use of more than 14 tablets per week was associated with a lower risk of BRAF-wild-type cancer (multivariable HR, 0.43; 95% CI, 0.25 to 0.75; age-adjusted incidence RD, -19.8; 95% CI, -26.3 to -13.3 per 100,000 person-years). The relationship between the number of aspirin tablets per week and colorectal cancer risk differed significantly by BRAF mutation status (P for heterogeneity = .005).Conclusions and relevanceRegular aspirin use was associated with lower risk of BRAF-wild-type colorectal cancer but not with BRAF-mutated cancer risk. These findings suggest that BRAF-mutant colon tumor cells may be less sensitive to the effect of aspirin. Given the modest absolute risk difference, further investigations are necessary to determine clinical implications of our findings.

Project description:ImportancePopulation-based East Asian data have corroborated reports from non-Asian settings on the association between low-dose aspirin and a lower risk of colorectal cancer (CRC).ObjectiveTo evaluate the association between duration and recency of low-dose aspirin use and CRC risk.Design, setting, and participantsThis nested case-control study included individuals who initiated aspirin use and matched individuals who did not use aspirin. Data were collected from Taiwan National Health Insurance and Taiwan Cancer Registry from 2000 through 2015. CRC cases were age- and sex-matched in a 1:4 ratio with individuals in a control group, identified from a cohort of individuals who used and did not use aspirin through risk-set sampling. Data analysis was conducted from June 2018 to July 2019.ExposuresLow-dose aspirin use was defined as receiving less than 150 mg per day, whereas 100 mg/d was most commonly used. Based on duration and recency of low-dose aspirin use between cohort entry (initiation date of low-dose aspirin for aspirin use group or randomly assigned date for those who did not use aspirin) and index date (CRC diagnosis date for individuals in the case group and the diagnosis date for the 4 corresponding matched individuals in the control group), the 3 following mutually exclusive exposure groups served as the basis for analysis: (1) long-term current low-dose aspirin use, (2) episodic low-dose aspirin use, and (3) no low-dose aspirin use (the reference group).Main outcomes and measuresCRC risk among the 3 exposure groups.ResultsAmong 4 710 504 individuals (2 747 830 [51.7%] men; median [interquartile range] age at cohort entry in initiator group, 61 [52-71] years; median [interquartile range] age at cohort entry in nonuse group, 59 [51-68] years), 79 095 CRC cases (1.7% of study cohort) were identified. Compared with no low-dose aspirin use, the adjusted odds ratio (OR) for long-term current low-dose aspirin use and CRC risk was 0.89 (95% CI, 0.85-0.93); for episodic use, 0.88 (95% CI, 0.86-0.89). Adjusted ORs of 0.69 (95% CI, 0.63-0.76) and 0.64 (95% CI, 0.61-0.67) were observed for long-term current use and episodic low-dose aspirin use within the subcohort of individuals who initiated low-dose aspirin between age 40 and 59 years.Conclusions and relevanceIn this study, low-dose aspirin use was associated with 11% lower CRC risk in an East Asian population, and this association was larger when low-dose aspirin use started before age 60 years.

Dataset Information

Association of aspirin and NSAID use with risk of colorectal cancer according to genetic variants.

Publications

Association of aspirin and NSAID use with risk of colorectal cancer according to genetic variants.

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