以往的调查主要集中在膳食脂肪酸与结直肠癌（CRC）风险的关联上，忽略了基因环境交互和机制解释。我们进行了一项病例对照研究（751例病例和3058名对照）和一项前瞻性队列研究（125021名参与者），以探讨膳食脂肪酸、基因风险和CRC之间的关联。结果显示，高饱和脂肪酸（SFA）摄入量与低SFA摄入量相比，与CRC的风险更高（HR=1.22，95% CI：1.02-1.46）。高基因风险的参与者比低基因风险的参与者更容易患上CRC，HR为2.48（2.11-2.91）。发现基因风险和SFA摄入之间的相乘交互作用与事件性CRC风险有关（P交互作用=7.59×10-20），表明高基因风险和高SFA摄入量的参与者比低基因风险和低SFA摄入量的参与者患CRC的风险高3.75倍。此外，将PRS和SFA纳入传统临床风险因素可提高CRC风险分层的判别准确性（AUC从0.706提高到0.731）。多组学数据显示，暴露于富含SFA的高脂饮食（HFD）中可以响应性地诱导某些癌基因的表观基因组重编程和脂肪酸代谢通路的病理性活化，可能通过肠道微生物、代谢物和肿瘤浸润免疫细胞的变化促进CRC的发展。这些发现表明，具有高CRC基因风险的个体应减少SFA的摄入。将SFA摄入和PRS纳入传统临床风险因素可帮助提高个体化CRC预防的高风险亚群。©2023年UICC。

Previous investigations mainly focused on the associations of dietary fatty acids with colorectal cancer (CRC) risk, which ignored gene-environment interaction and mechanisms interpretation. We conducted a case-control study (751 cases and 3058 controls) and a prospective cohort study (125 021 participants) to explore the associations between dietary fatty acids, genetic risks, and CRC. Results showed that high intake of saturated fatty acid (SFA) was associated with a higher risk of CRC than low SFA intake (HR =1.22, 95% CI:1.02-1.46). Participants at high genetic risk had a greater risk of CRC with the HR of 2.48 (2.11-2.91) than those at low genetic risk. A multiplicative interaction of genetic risk and SFA intake with incident CRC risk was found (PInteraction  = 7.59 × 10-20 ), demonstrating that participants with high genetic risk and high SFA intake had a 3.75-fold greater risk of CRC than those with low genetic risk and low SFA intake. Furthermore, incorporating PRS and SFA into traditional clinical risk factors improved the discriminatory accuracy for CRC risk stratification (AUC from 0.706 to 0.731). Multi-omics data showed that exposure to SFA-rich high-fat dietary (HFD) can responsively induce epigenome reprogramming of some oncogenes and pathological activation of fatty acid metabolism pathway, which may contribute to CRC development through changes in gut microbiomes, metabolites, and tumor-infiltrating immune cells. These findings suggest that individuals with high genetic risk of CRC may benefit from reducing SFA intake. The incorporation of SFA intake and PRS into traditional clinical risk factors will help improve high-risk sub-populations in individualized CRC prevention.© 2023 UICC.