Reduced levels of hydroxylated, polyunsaturated ultra long-chain fatty acids in the serum of colorectal cancer patients: implications for early screening and detection

Abstract

BackgroundThere 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.MethodsBiomarker 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).ResultsComprehensive 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).ConclusionsA 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.

Metabolomic NMR Fingerprinting to Identify and Predict Survival of Patients with Metastatic Colorectal Cancer

“…Reduced levels of hydroxylated, polyunsaturated ultra long-chain fatty acids have been reported for patients with CRC on the basis of NMR/MS studies and proposed as a signature of this disease (21).…”

“…In recent years, metabolomic studies have provided a significant contribution to the detailed understanding of the biochemical network and pathways in oncology (11), highlighting the potential of metabolomic analyses of blood samples for the detection of cancers, including epithelial ovarian (12), leukemia (13), oral (14), breast (15,16), prostate (11), liver (17) as well as colorectal cancer (CRC; refs. [18][19][20][21][22][23][24][25]. CRC is the second most common cause of cancer-related deaths in Europe (26) and the third most common cause of cancerrelated deaths in the United States (27).…”

“…The impact of colorectal carcinogenesis on the metabolic profile of tissues and serum has been tested by mass spectrometry (MS; refs. [18][19][20][21], nuclear magnetic resonance (NMR; refs. 22,23), or a combination of the two analytic tools (24).…”

Applications of liquid chromatography coupled to mass spectrometry-based metabolomics in clinical chemistry and toxicology: A review

“…Richie et al [119] applied both targeted and non targeted metabolomics-based approaches in order to identify non invasive biomarkers of colorectal cancer (CRC). They started with a large-scale study on serum samples from several populations of different origins.…”

Metabolomics for tumor marker discovery and identification based on chromatography–mass spectrometry

“…Review MS-based metabolomic platforms are increasingly applied to the screening of tumor markers and have been used in recent years for colorectal cancer [39][40][41][42][43][44][45][46], lung cancer [47][48][49][50][51][52][53], papillary thyroid carcinoma [54], oral cancer [55,56] and pancreatic cancer [57]. Here, due to space limitations, the authors review the development of metabolomics in the discovery of tumor markers only for specific malignancies with high incidence, including primary liver cancer, gynecologic cancer and genitourinary cancer.…”