Diacetylspermine Is a Novel Prediagnostic Serum Biomarker for Non-Small-Cell Lung Cancer and Has Additive Performance With Pro-Surfactant Protein B.
OBJECTIVE
We have investigated the potential of metabolomics to discover blood-based biomarkers relevant to lung cancer screening and early detection. An untargeted metabolomics approach was applied to identify biomarker candidates using prediagnostic sera from the Beta-Carotene and Retinol Efficacy Trial (CARET) study.


METHODS
A liquid chromatography/mass spectrometry hydrophilic interaction method designed to profile a wide range of metabolites was applied to prediagnostic serum samples from CARET participants (current or former heavy smokers), consisting of 100 patients who subsequently developed non-small-cell lung cancer (NSCLC) and 199 matched controls. A separate aliquot was used to quantify levels of pro-surfactant protein B (pro-SFTPB), a previously established protein biomarker for NSCLC. On the basis of the results from the discovery set, blinded validation of a metabolite, identified as N(1),N(12)-diacetylspermine (DAS), and pro-SFTPB was performed using an independent set of CARET prediagnostic sera from 108 patients with NSCLC and 216 matched controls.


RESULTS
Serum DAS was elevated by 1.9-fold, demonstrating significant specificity and sensitivity in the discovery set for samples collected up to 6 months before diagnosis of NSCLC. In addition, DAS significantly complemented performance of pro-SFTPB in both the discovery and validations sets, with a combined area under the curve in the validation set of 0.808 (P < .001 v pro-SFTPB).


CONCLUSIONS
DAS is a novel serum metabolite with significant performance in prediagnostic NSCLC and has additive performance with pro-SFTPB.
William R. Wikoff, Brian DeFelice, and Oliver Fiehn, National Institutes of Health West Coast Metabolomics Center, University of California, Davis, Davis; Suzanne Miyamoto and David Gandara, University of California, Davis, Davis Comprehensive Cancer Center, Sacramento, CA; Samir Hanash, Yang Zhao, Ziding Feng, and Ayumu Taguchi, The University of Texas MD Anderson Cancer Center, Houston, TX; and Matt Barnett and Gary Goodman, Fred Hutchison Cancer Research Center, Seattle, WA.
William R
WR
Wikoff
William R. Wikoff, Brian DeFelice, and Oliver Fiehn, National Institutes of Health West Coast Metabolomics Center, University of California, Davis, Davis; Suzanne Miyamoto and David Gandara, University of California, Davis, Davis Comprehensive Cancer Center, Sacramento, CA; Samir Hanash, Yang Zhao, Ziding Feng, and Ayumu Taguchi, The University of Texas MD Anderson Cancer Center, Houston, TX; and Matt Barnett and Gary Goodman, Fred Hutchison Cancer Research Center, Seattle, WA.
Samir
S
Hanash
William R. Wikoff, Brian DeFelice, and Oliver Fiehn, National Institutes of Health West Coast Metabolomics Center, University of California, Davis, Davis; Suzanne Miyamoto and David Gandara, University of California, Davis, Davis Comprehensive Cancer Center, Sacramento, CA; Samir Hanash, Yang Zhao, Ziding Feng, and Ayumu Taguchi, The University of Texas MD Anderson Cancer Center, Houston, TX; and Matt Barnett and Gary Goodman, Fred Hutchison Cancer Research Center, Seattle, WA.
Brian
B
DeFelice
William R. Wikoff, Brian DeFelice, and Oliver Fiehn, National Institutes of Health West Coast Metabolomics Center, University of California, Davis, Davis; Suzanne Miyamoto and David Gandara, University of California, Davis, Davis Comprehensive Cancer Center, Sacramento, CA; Samir Hanash, Yang Zhao, Ziding Feng, and Ayumu Taguchi, The University of Texas MD Anderson Cancer Center, Houston, TX; and Matt Barnett and Gary Goodman, Fred Hutchison Cancer Research Center, Seattle, WA.
Suzanne
S
Miyamoto
William R. Wikoff, Brian DeFelice, and Oliver Fiehn, National Institutes of Health West Coast Metabolomics Center, University of California, Davis, Davis; Suzanne Miyamoto and David Gandara, University of California, Davis, Davis Comprehensive Cancer Center, Sacramento, CA; Samir Hanash, Yang Zhao, Ziding Feng, and Ayumu Taguchi, The University of Texas MD Anderson Cancer Center, Houston, TX; and Matt Barnett and Gary Goodman, Fred Hutchison Cancer Research Center, Seattle, WA.
Matt
M
Barnett
William R. Wikoff, Brian DeFelice, and Oliver Fiehn, National Institutes of Health West Coast Metabolomics Center, University of California, Davis, Davis; Suzanne Miyamoto and David Gandara, University of California, Davis, Davis Comprehensive Cancer Center, Sacramento, CA; Samir Hanash, Yang Zhao, Ziding Feng, and Ayumu Taguchi, The University of Texas MD Anderson Cancer Center, Houston, TX; and Matt Barnett and Gary Goodman, Fred Hutchison Cancer Research Center, Seattle, WA.
Yang
Y
Zhao
William R. Wikoff, Brian DeFelice, and Oliver Fiehn, National Institutes of Health West Coast Metabolomics Center, University of California, Davis, Davis; Suzanne Miyamoto and David Gandara, University of California, Davis, Davis Comprehensive Cancer Center, Sacramento, CA; Samir Hanash, Yang Zhao, Ziding Feng, and Ayumu Taguchi, The University of Texas MD Anderson Cancer Center, Houston, TX; and Matt Barnett and Gary Goodman, Fred Hutchison Cancer Research Center, Seattle, WA.
Gary
G
Goodman
William R. Wikoff, Brian DeFelice, and Oliver Fiehn, National Institutes of Health West Coast Metabolomics Center, University of California, Davis, Davis; Suzanne Miyamoto and David Gandara, University of California, Davis, Davis Comprehensive Cancer Center, Sacramento, CA; Samir Hanash, Yang Zhao, Ziding Feng, and Ayumu Taguchi, The University of Texas MD Anderson Cancer Center, Houston, TX; and Matt Barnett and Gary Goodman, Fred Hutchison Cancer Research Center, Seattle, WA.
Ziding
Z
Feng
William R. Wikoff, Brian DeFelice, and Oliver Fiehn, National Institutes of Health West Coast Metabolomics Center, University of California, Davis, Davis; Suzanne Miyamoto and David Gandara, University of California, Davis, Davis Comprehensive Cancer Center, Sacramento, CA; Samir Hanash, Yang Zhao, Ziding Feng, and Ayumu Taguchi, The University of Texas MD Anderson Cancer Center, Houston, TX; and Matt Barnett and Gary Goodman, Fred Hutchison Cancer Research Center, Seattle, WA.
David
D
Gandara
William R. Wikoff, Brian DeFelice, and Oliver Fiehn, National Institutes of Health West Coast Metabolomics Center, University of California, Davis, Davis; Suzanne Miyamoto and David Gandara, University of California, Davis, Davis Comprehensive Cancer Center, Sacramento, CA; Samir Hanash, Yang Zhao, Ziding Feng, and Ayumu Taguchi, The University of Texas MD Anderson Cancer Center, Houston, TX; and Matt Barnett and Gary Goodman, Fred Hutchison Cancer Research Center, Seattle, WA. ofiehn@ucdavis.edu.
Oliver
O
Fiehn
William R. Wikoff, Brian DeFelice, and Oliver Fiehn, National Institutes of Health West Coast Metabolomics Center, University of California, Davis, Davis; Suzanne Miyamoto and David Gandara, University of California, Davis, Davis Comprehensive Cancer Center, Sacramento, CA; Samir Hanash, Yang Zhao, Ziding Feng, and Ayumu Taguchi, The University of Texas MD Anderson Cancer Center, Houston, TX; and Matt Barnett and Gary Goodman, Fred Hutchison Cancer Research Center, Seattle, WA.
Ayumu
A
Taguchi
D000368:Aged; D014408:Biomarkers, Tumor / Q000097:blood*; D002289:Carcinoma, Non-Small-Cell Lung / Q000097:blood* / Q000453:epidemiology / Q000503:physiopathology; D016022:Case-Control Studies; D002853:Chromatography, Liquid / Q000379:methods; D018572:Disease-Free Survival; D055088:Early Detection of Cancer / Q000379:methods*; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000097:blood* / Q000453:epidemiology / Q000503:physiopathology; D008297:Male; D013058:Mass Spectrometry / Q000379:methods; D008875:Middle Aged; D011379:Prognosis; D011498:Protein Precursors / Q000097:blood*; D037661:Pulmonary Surfactant-Associated Proteins / Q000097:blood*; D012372:ROC Curve; D018570:Risk Assessment; D012680:Sensitivity and Specificity; D012907:Smoking / Q000009:adverse effects / Q000097:blood; D013096:Spermine / Q000031:analogs & derivatives* / Q000097:blood; D018709:Statistics, Nonparametric; D016019:Survival Analysis
D014408:Biomarkers, Tumor; D011498:Protein Precursors; D037661:Pulmonary Surfactant-Associated Proteins; C586477:SFTPB protein, human; D013096:Spermine; C029453:N',N''-diacetylspermine