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


METHODS
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).


RESULTS
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).


CONCLUSIONS
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.
Ritchie
Shawn A
SA
Phenomenome Discoveries Inc, Saskatoon, SK, Canada. s.ritchie@phenomenome.com
Ahiahonu
Pearson W K
PW
Jayasinghe
Dushmanthi
D
Heath
Doug
D
Liu
Jun
J
Lu
Yingshen
Y
Jin
Wei
W
Kavianpour
Amir
A
Yamazaki
Yasuyo
Y
Khan
Amin M
AM
Hossain
Mohammad
M
Su-Myat
Khine Khine
KK
Wood
Paul L
PL
Krenitsky
Kevin
K
Takemasa
Ichiro
I
Miyake
Masakazu
M
Sekimoto
Mitsugu
M
Monden
Morito
M
Matsubara
Hisahiro
H
Nomura
Fumio
F
Goodenowe
Dayan B
DB
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000097:blood*; D016022:Case-Control Studies; D015179:Colorectal Neoplasms / Q000097:blood* / Q000175:diagnosis; D055088:Early Detection of Cancer / Q000379:methods*; D005231:Fatty Acids, Unsaturated / Q000097:blood*; D005260:Female; D006801:Humans; D006900:Hydroxylation; D016018:Least-Squares Analysis; D008297:Male; D013058:Mass Spectrometry / Q000379:methods; D055442:Metabolome; D008875:Middle Aged; D008970:Molecular Weight; D019906:Nuclear Magnetic Resonance, Biomolecular; D015203:Reproducibility of Results; D012680:Sensitivity and Specificity; D017550:Spectroscopy, Fourier Transform Infrared / Q000379:methods
D014408:Biomarkers, Tumor; D005231:Fatty Acids, Unsaturated