Department of Epidemiology & Biostatistics, Memorial Sloan Kettering Cancer Center, New York, New York.
Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt University School of Medicine, Nashville, Tennessee.
Cancer Epidemiol Biomarkers Prev. 2022 Jun 1;31(6):1216-1226. doi: 10.1158/1055-9965.EPI-21-1008.
The etiology of colorectal cancer is not fully understood.
Using genetic variants and metabolomics data including 217 metabolites from the Framingham Heart Study (n = 1,357), we built genetic prediction models for circulating metabolites. Models with prediction R2 > 0.01 (Nmetabolite = 58) were applied to predict levels of metabolites in two large consortia with a combined sample size of approximately 46,300 cases and 59,200 controls of European and approximately 21,700 cases and 47,400 controls of East Asian (EA) descent. Genetically predicted levels of metabolites were evaluated for their associations with colorectal cancer risk in logistic regressions within each racial group, after which the results were combined by meta-analysis.
Of the 58 metabolites tested, 24 metabolites were significantly associated with colorectal cancer risk [Benjamini-Hochberg FDR (BH-FDR) < 0.05] in the European population (ORs ranged from 0.91 to 1.06; P values ranged from 0.02 to 6.4 × 10-8). Twenty one of the 24 associations were replicated in the EA population (ORs ranged from 0.26 to 1.69, BH-FDR < 0.05). In addition, the genetically predicted levels of C16:0 cholesteryl ester was significantly associated with colorectal cancer risk in the EA population only (OREA: 1.94, 95% CI, 1.60-2.36, P = 2.6 × 10-11; OREUR: 1.01, 95% CI, 0.99-1.04, P = 0.3). Nineteen of the 25 metabolites were glycerophospholipids and triacylglycerols (TAG). Eighteen associations exhibited significant heterogeneity between the two racial groups (PEUR-EA-Het < 0.005), which were more strongly associated in the EA population. This integrative study suggested a potential role of lipids, especially certain glycerophospholipids and TAGs, in the etiology of colorectal cancer.
This study identified potential novel risk biomarkers for colorectal cancer by integrating genetics and circulating metabolomics data.
The identified metabolites could be developed into new tools for risk assessment of colorectal cancer in both European and EA populations.
结直肠癌的病因尚未完全阐明。
利用来自弗雷明汉心脏研究（n=1357）的 217 种代谢物的遗传变异和代谢组学数据，我们为循环代谢物建立了遗传预测模型。预测 R2>0.01（Nmetabolite=58）的模型应用于两个大型联盟中代谢物水平的预测，这两个联盟的样本量总和约为 46300 例欧洲裔和 21700 例东亚裔（EA）结直肠癌病例和 59200 例和 47400 例对照。在每个种族群体中，通过逻辑回归评估遗传预测的代谢物水平与结直肠癌风险的关联，然后通过荟萃分析合并结果。
在欧洲人群中，24 种代谢物与结直肠癌风险显著相关（Benjamini-Hochberg FDR（BH-FDR）<0.05；OR 范围为 0.91 至 1.06；P 值范围为 0.02 至 6.4×10-8）。24 个关联中有 21 个在东亚人群中得到复制（OR 范围为 0.26 至 1.69，BH-FDR<0.05）。此外，在东亚人群中，C16:0 胆甾醇酯的遗传预测水平与结直肠癌风险显著相关（OREA：1.94，95%CI，1.60-2.36，P=2.6×10-11；OREUR：1.01，95%CI，0.99-1.04，P=0.3）。25 种代谢物中有 19 种为甘油磷脂和三酰甘油（TAG）。25 个关联中有 18 个在两个种族群体之间存在显著异质性（PEUR-EA-Het<0.005），在东亚人群中相关性更强。这项综合研究表明脂质，特别是某些甘油磷脂和 TAG，可能在结直肠癌的病因中起作用。
本研究通过整合遗传学和循环代谢组学数据，发现了结直肠癌潜在的新型风险生物标志物。
所鉴定的代谢物可开发为欧洲和东亚人群结直肠癌风险评估的新工具。
