Leeds Institute of Medical Research, University of Leeds, Leeds, United Kingdom.
Nutrition and Preventive Medicine, Norwich Medical School, University of East Anglia, Norwich, United Kingdom.
Cancer Prev Res (Phila). 2023 Nov 1;16(11):621-629. doi: 10.1158/1940-6207.CAPR-23-0111.
Aspirin and eicosapentaenoic acid (EPA) reduce colorectal adenomatous polyp risk and affect synthesis of oxylipins including prostaglandin E2. We investigated whether 35 SNPs in oxylipin metabolism genes such as cyclooxygenase (PTGS) and lipoxygenase (ALOX), as well as 7 SNPs already associated with colorectal cancer risk reduction by aspirin (e.g., TP53; rs104522), modified the effects of aspirin and EPA on colorectal polyp recurrence in the randomized 2 × 2 factorial seAFOod trial. Treatment effects were reported as the incidence rate ratio (IRR) and 95% confidence interval (CI) by stratifying negative binomial and Poisson regression analyses of colorectal polyp risk on SNP genotype. Statistical significance was reported with adjustment for the false discovery rate as the P and q value. 542 (of 707) trial participants had both genotype and colonoscopy outcome data. Reduction in colorectal polyp risk in aspirin users compared with nonaspirin users was restricted to rs4837960 (PTGS1) common homozygotes [IRR, 0.69; 95% confidence interval (CI), 0.53-0.90); q = 0.06], rs2745557 (PTGS2) compound heterozygote-rare homozygotes [IRR, 0.60 (0.41-0.88); q = 0.06], rs7090328 (ALOX5) rare homozygotes [IRR 0.27 (0.11-0.64); q = 0.05], rs2073438 (ALOX12) common homozygotes [IRR, 0.57 (0.41-0.80); q = 0.05], and rs104522 (TP53) rare homozygotes [IRR, 0.37 (0.17-0.79); q = 0.06]. No modification of colorectal polyp risk in EPA users was observed. In conclusion, genetic variants relevant to the proposed mechanism of action on oxylipins are associated with differential colorectal polyp risk reduction by aspirin in individuals who develop multiple colorectal polyps. SNP genotypes should be considered during development of personalized, predictive models of colorectal cancer chemoprevention by aspirin.
Single-nucleotide polymorphisms in genes controlling lipid mediator signaling may modify the colorectal polyp prevention activity of aspirin. Further investigation is required to determine whether testing for genetic variants can be used to target cancer chemoprevention by aspirin to those who will benefit most.
背景：阿司匹林和二十碳五烯酸（EPA）可降低结直肠腺瘤性息肉的风险，并影响包括前列腺素 E2 在内的氧化脂类的合成。我们研究了氧化脂类代谢基因（如环氧化酶[PTGS]和脂氧合酶[ALOX]）中的 35 个单核苷酸多态性（SNP），以及 7 个与阿司匹林降低结直肠癌风险相关的 SNP（如 TP53；rs104522），是否改变了阿司匹林和 EPA 对随机 2×2 析因 seAFOod 试验中结直肠息肉复发的影响。通过对结直肠息肉风险进行负二项式和泊松回归分析的分层，将治疗效果报告为发生率比（IRR）和 95%置信区间（CI）。通过调整假发现率报告 SNP 基因型的统计学意义，P 值和 q 值。542（707）名试验参与者均具有基因型和结肠镜检查结果数据。与非阿司匹林使用者相比，阿司匹林使用者结直肠息肉风险降低仅限于 rs4837960（PTGS1）常见纯合子[IRR，0.69；95%置信区间（CI），0.53-0.90）；q = 0.06]，rs2745557（PTGS2）复合杂合子-罕见纯合子[IRR，0.60（0.41-0.88）；q = 0.06]，rs7090328（ALOX5）罕见纯合子[IRR 0.27（0.11-0.64）；q = 0.05]，rs2073438（ALOX12）常见纯合子[IRR，0.57（0.41-0.80）；q = 0.05]和 rs104522（TP53）罕见纯合子[IRR，0.37（0.17-0.79）；q = 0.06]。在 EPA 使用者中未观察到结直肠息肉风险的改变。结论：与氧化脂类作用机制相关的基因中的遗传变异与阿司匹林在发生多发性结直肠息肉的个体中降低结直肠息肉风险有关。在开发阿司匹林结直肠癌化学预防的个体化、预测模型时，应考虑 SNP 基因型。
意义：控制脂质介质信号的基因中的单核苷酸多态性可能会改变阿司匹林对结直肠息肉预防的作用。需要进一步研究以确定是否可以通过检测遗传变异来针对阿司匹林对大多数受益人群的癌症化学预防。
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