Phenomenome Discoveries Inc, Saskatoon, SK, Canada.
BMC Med. 2010 Feb 15;8:13. doi: 10.1186/1741-7015-8-13.
There are currently no accurate serum markers for detecting early risk of colorectal cancer (CRC). We therefore developed a non-targeted metabolomics technology to analyse the serum of pre-treatment CRC patients in order to discover putative metabolic markers associated with CRC. Using tandem-mass spectrometry (MS/MS) high throughput MS technology we evaluated the utility of selected markers and this technology for discriminating between CRC and healthy subjects.
Biomarker discovery was performed using Fourier transform ion cyclotron resonance mass spectrometry (FTICR-MS). Comprehensive metabolic profiles of CRC patients and controls from three independent populations from different continents (USA and Japan; total n = 222) were obtained and the best inter-study biomarkers determined. The structural characterization of these and related markers was performed using liquid chromatography (LC) MS/MS and nuclear magnetic resonance technologies. Clinical utility evaluations were performed using a targeted high-throughput triple-quadrupole multiple reaction monitoring (TQ-MRM) method for three biomarkers in two further independent populations from the USA and Japan (total n = 220).
Comprehensive metabolomic analyses revealed significantly reduced levels of 28-36 carbon-containing hydroxylated polyunsaturated ultra long-chain fatty-acids in all three independent cohorts of CRC patient samples relative to controls. Structure elucidation studies on the C28 molecules revealed two families harbouring specifically two or three hydroxyl substitutions and varying degrees of unsaturation. The TQ-MRM method successfully validated the FTICR-MS results in two further independent studies. In total, biomarkers in five independent populations across two continental regions were evaluated (three populations by FTICR-MS and two by TQ-MRM). The resultant receiver-operator characteristic curve AUCs ranged from 0.85 to 0.98 (average = 0.91 +/- 0.04).
A novel comprehensive metabolomics technology was used to identify a systemic metabolic dysregulation comprising previously unknown hydroxylated polyunsaturated ultra-long chain fatty acid metabolites in CRC patients. These metabolites are easily measurable in serum and a decrease in their concentration appears to be highly sensitive and specific for the presence of CRC, regardless of ethnic or geographic background. The measurement of these metabolites may represent an additional tool for the early detection and screening of CRC.
目前尚无准确的血清标志物可用于检测结直肠癌（CRC）的早期风险。因此，我们开发了一种非靶向代谢组学技术来分析治疗前 CRC 患者的血清，以发现与 CRC 相关的潜在代谢标志物。我们使用串联质谱（MS/MS）高通量 MS 技术评估了选定标志物和该技术在区分 CRC 患者和健康受试者方面的效用。
使用傅立叶变换离子回旋共振质谱（FTICR-MS）进行生物标志物发现。从三个不同大陆（美国和日本；总 n=222）的三个独立人群中获得 CRC 患者和对照者的综合代谢谱，并确定最佳的跨研究生物标志物。使用液相色谱（LC）MS/MS 和核磁共振技术对这些和相关标志物进行结构特征分析。使用来自美国和日本的另外两个独立人群的针对三种生物标志物的靶向高通量三重四极杆多重反应监测（TQ-MRM）方法进行临床效用评估（总 n=220）。
全面代谢组学分析显示，与对照组相比，所有三个独立的 CRC 患者样本队列中 28-36 个碳原子含量的羟基化多不饱和超长链脂肪酸的水平明显降低。对 C28 分子的结构阐明研究揭示了两个家族，它们分别含有两个或三个羟基取代基和不同程度的不饱和性。TQ-MRM 方法在另外两个独立研究中成功验证了 FTICR-MS 结果。总共在两个大陆地区的五个独立人群中评估了标志物（三个人群通过 FTICR-MS，两个人群通过 TQ-MRM）。由此产生的接收器操作特征曲线 AUC 范围为 0.85 至 0.98（平均值=0.91+/-0.04）。
使用一种新的全面代谢组学技术，我们发现 CRC 患者存在系统性代谢失调，包括以前未知的羟基化多不饱和超长链脂肪酸代谢物。这些代谢物在血清中易于测量，其浓度的降低似乎对 CRC 的存在具有高度的敏感性和特异性，无论种族或地理背景如何。这些代谢物的测量可能代表 CRC 早期检测和筛查的另一种工具。
