MRC Integrative Epidemiology Unit at the University of Bristol, Bristol, United Kingdom.
Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, United Kingdom.
Elife. 2023 Dec 21;12:RP87894. doi: 10.7554/eLife.87894.
Recognizing the early signs of cancer risk is vital for informing prevention, early detection, and survival.
To investigate whether changes in circulating metabolites characterize the early stages of colorectal cancer (CRC) development, we examined the associations between a genetic risk score (GRS) associated with CRC liability (72 single-nucleotide polymorphisms) and 231 circulating metabolites measured by nuclear magnetic resonance spectroscopy in the Avon Longitudinal Study of Parents and Children (N = 6221). Linear regression models were applied to examine the associations between genetic liability to CRC and circulating metabolites measured in the same individuals at age 8 y, 16 y, 18 y, and 25 y.
The GRS for CRC was associated with up to 28% of the circulating metabolites at FDR-P < 0.05 across all time points, particularly with higher fatty acids and very-low- and low-density lipoprotein subclass lipids. Two-sample reverse Mendelian randomization (MR) analyses investigating CRC liability (52,775 cases, 45,940 controls) and metabolites measured in a random subset of UK Biobank participants (N = 118,466, median age 58 y) revealed broadly consistent effect estimates with the GRS analysis. In conventional (forward) MR analyses, genetically predicted polyunsaturated fatty acid concentrations were most strongly associated with higher CRC risk.
These analyses suggest that higher genetic liability to CRC can cause early alterations in systemic metabolism and suggest that fatty acids may play an important role in CRC development.
This work was supported by the Elizabeth Blackwell Institute for Health Research, University of Bristol, the Wellcome Trust, the Medical Research Council, Diabetes UK, the University of Bristol NIHR Biomedical Research Centre, and Cancer Research UK. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. This work used the computational facilities of the Advanced Computing Research Centre, University of Bristol - http://www.bristol.ac.uk/acrc/.
识别癌症风险的早期迹象对于告知预防、早期发现和生存至关重要。
为了研究循环代谢物的变化是否能描述结直肠癌（CRC）发展的早期阶段，我们通过核磁共振光谱法检测了阿冯纵向父母和儿童研究（Avon Longitudinal Study of Parents and Children，N=6221）中 231 种循环代谢物，并研究了与 CRC 易感性相关的遗传风险评分（genetic risk score，GRS）（72 个单核苷酸多态性）与在同一个体中 8 岁、16 岁、18 岁和 25 岁时测量的循环代谢物之间的关联。应用线性回归模型检验了 CRC 遗传易感性与在所有时间点 FDR-P<0.05 下测量的循环代谢物之间的关系。
CRC 的 GRS 与高达 28%的循环代谢物相关，尤其是与更高的脂肪酸和极低密度脂蛋白和低密度脂蛋白亚类脂质相关。两项两样本反向孟德尔随机化（MR）分析分别调查了 CRC 易感性（52775 例病例，45940 例对照）和在英国生物银行参与者的随机子集中测量的代谢物（N=118466 人，中位年龄 58 岁），与 GRS 分析结果一致。在传统的（正向）MR 分析中，遗传预测的多不饱和脂肪酸浓度与更高的 CRC 风险关系最为密切。
这些分析表明，CRC 的遗传易感性升高可能导致全身代谢的早期改变，并表明脂肪酸可能在 CRC 发展中起重要作用。
这项工作得到了布里斯托伊丽莎白布莱克威尔健康研究所、惠康信托基金会、医学研究理事会、英国糖尿病协会、布里斯托大学英国国家健康研究所生物医学研究中心以及英国癌症研究中心的支持。资助者在研究设计、数据收集和分析、出版决定或手稿准备方面没有任何作用。这项工作使用了布里斯托大学高级计算研究中心的计算设施 - http://www.bristol.ac.uk/acrc/。
