Cancer Res Treat.  2018 Jul;50(3):883-893. 10.4143/crt.2017.275.

Profiling of Serum Metabolites Using MALDI-TOF and Triple-TOF Mass Spectrometry to Develop a Screen for Ovarian Cancer

• Lee JH
• Kim YH
• Kim KH
• Cho JY
• Woo SM
• Yoo BC
• Kim SC

• KMID: 2417877
• DOI: http://doi.org/10.4143/crt.2017.275

Abstract

PURPOSE
We sought to develop a matrix assisted laser desorption ionization-time of flight (MALDI-TOF)-based, ovarian cancer (OVC), low-mass-ion discriminant equation (LOME) and to evaluate a possible supportive role for triple-TOF mass analysis in identifying metabolic biomarkers.
MATERIALS AND METHODS
A total of 114 serum samples from patients with OVC and benign ovarian tumors were subjected to MALDI-TOF analysis and a total of 137 serum samples from healthy female individuals and patients with OVC, colorectal cancer, hepatobiliary cancer, and pancreatic cancer were subjected to triple-TOF analysis. An OVC LOME was constructed by reference to the peak intensity ratios of discriminatory low-mass ion (LMI) pairs. Triple-TOF analysiswas used to select and identify metabolic biomarkers for OVC screening.
RESULTS
Three OVC LOMEs were finally constructed using discriminatory LMI pairs (137.1690 and 84.4119 m/z; 496.5022 and 709.7642 m/z; and 524.5614 and 709.7642 m/z); all afforded accuracies of > 90%. The LMIs at 496.5022 m/z and 524.5614 m/z were those of lysophosphatidylcholine (LPC) 16:0 and LPC 18:0. Triple-TOF analysis selected seven discriminative LMIs; each LMI had a specificity > 90%. Of the seven LMIs, fourwith a 137.0455 m/z ion atretention times of 2.04-3.14 minuteswere upregulated in sera from OVC patients; the ion was identified as that derived from hypoxanthine.
CONCLUSION
MALDI-TOF-based OVC LOMEs combined with triple-TOF-based OVC metabolic biomarkers allow reliable OVC screening; the techniques are mutually complementary both quantitatively and qualitatively.

Keyword

Ovarian neoplasms; Low-mass ions; Serum metabolite; Hypoxanthine; Mass spectrometry

MeSH Terms

Biomarkers
Colorectal Neoplasms
Female
Humans
Hypoxanthine
Lysophosphatidylcholines
Mass Screening
Mass Spectrometry*
Ovarian Neoplasms*
Pancreatic Neoplasms
Sensitivity and Specificity
Biomarkers
Hypoxanthine
Lysophosphatidylcholines

Figure

• 

  Fig. 1. Separation results obtained during one of the six repeats of matrix assisted laser desorption ionization-time of flight analysis. (A) Principal component analysis-based discriminant analysis (PCA-DA). (B) Preliminary low-mass-ion candidates. DS, discriminant score; OVC, ovarian cancer; BOT, benign ovarian tumor.

• 

  Fig. 2. Discriminatory results afforded by the ratios of low-mass ion pairs on matrix assisted laser desorption ionization-time of flight analysis. (A) Log10(137.1690 m/z)/Log10(84.4119 m/z). (B) Log10(496.5022 m/z)/Log10(709.7642 m/z). (C) Log10 (524.5614 m/z)/Log10(709.7642 m/z). OVC, ovarian cancer; BOT, benign ovarian tumor.

• 

  Fig. 3. Seven candidate metabolites suggested by triple-TOF analysis to be characteristic of ovarian cancer (OVC). (A) Figure shows relative amount of each candidate metabolites [Y-axis, Log10(mass peak area of low-mass ion)] in healthy women (control) and those with OVC, colorectal cancer (CRC), hepatobiliary cancer (HBC), and pancreatic cancer (PC). Low-mass ions (LMIs) of 137.0455 m/z, retention time (RT) 2.04 min; 138.0497 m/z, RT 2.46 min; 159.0270 m/z, RT 2.46 min; 137.0461 m/z, RT 2.07 min; 137.0454 m/z, RT 3.14 min; 359.1413 m/z, RT 15.27 min; 381.1314 m/z, RT 15.30 min. Of the seven LMIs, four with a 137.0455 m/z ion at RTs of 2.04-3.14 min were upregulated in sera from OVC patients; those LMIs were identified as hypoxanthine. (B) A volcano plot of low-mass ions detected on triple-TOF analysis.

• 

  Fig. 4. Identification of hypoxanthine upregulated in sera of ovarian cancer (OVC) patients. A low-mass ion of 137.0455 m/z (left panel, B) exhibited a retention time (RT) that differed slightly from that of hypoxanthine (left panel, A), but the tandem mass spectrometry (MS/MS) pattern (right panel, B) was exactly that of hypoxanthine (right panel, A).

Reference

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