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Citation Information

  • Lung Cancer. 2011 Nov;74(2):284-92. doi: 10.1016/j.lungcan.2011.02.008. Epub 2011 Mar 15.

  • A metabolomic approach to lung cancer.

  • Hori S, Nishiumi S, Kobayashi K, Shinohara M, Hatakeyama Y, Kotani Y, Hatano N, Maniwa Y, Nishio W, Bamba T, Fukusaki E, Azuma T, Takenawa T, Nishimura Y, Yoshida M.


Analytical methods

Comparative study #1 #2 #3 #4
Chromatography GC GC GC GC
Ion source – – – –
Positive/Negative mode – – – –
Mass analyzer – – – –
Identification level – – – –

Sample information

Comparative study #1 #2 #3 #4
Country Japan Japan Japan Japan
Specimen serum serum serum tissue
Marker function diagnosis diagnosis diagnosis diagnosis
Participants(Case) Cancer type adenocarcinoma, squamous cell carcinoma, SCLC adenocarcinoma, squamous cell carcinoma, SCLC adenocarcinoma, squamous cell carcinoma, SCLC adenocarcinoma, squamous cell carcinoma, SCLC
StageI, II, III, IVI, IIIII, IV–
Number3311227
Gender (M,F)26, 7––6, 1
Mean age (range) (M,F)median: 65 (55-81)––median: 61 (53-82)
Smoking statussmoker, non-smoker, unknown––smoker, non-smoker
Participants(Control) Type healthy healthy healthy tumor vs. adjacent normal tissue
Number2929297
Gender (M,F)23, 623, 623, 66, 1
Mean age (range) (M,F)median: 64 (34-78)median: 64 (34-78)median: 64 (34-78)median: 61 (53-82)
Smoking statussmoker, non-smoker, unknownsmoker, non-smoker, unknownsmoker, non-smoker, unknownsmoker, non-smoker

Data processing and metabolite identification

Data processing software Shimadzu GCMSsolution software
Database search commercially available GC/MS Metabolite Mass Spectral Database (Shimadzu Co.), NIST Mass Spectral Library (NIST 08)

Statistical analysis

Differential analysis method student’s t-test, PLS-DA
Classification method –
Survival analysis method –

Lung cancer-related metabolites identified in the paper

Metabolite Author-emphasized biomarkers Mean concentration (case) Mean concentration (control) Fold change (case/control) P-value FDR VIP
L-tryptophan – – – 4.43 0.02 – –
L-cysteine – – – 3.26 0.02 – –
asparagine – – – 3.05 0.09 – –
4-hydroxyphenyllactic acid – – – 2.95 4.00e-03 – –
uric acid V – – 2.84 7.00e-04 – –
D-ribose – – – 2.66 5.00e-03 – –
L-glutamine – – – 2.54 0.02 – –
L-tyrosine – – – 2.43 0.01 – –
3-hydroxybutyric acid V – – 2.41 3.80e-03 – –
α-aminoadipic acid – – – 2.36 1.00e-02 – –
uric acid V – – 2.33 7.00e-04 – –
aminomalonic acid – – – 2.32 0.01 – –
N-acetyl glucosamine – – – 2.31 0.06 – –
L-glutamic acid V – – 2.31 3.00e-03 – –
2-hydroxyglutaric acid – – – 2.29 2.00e-03 – –
D-glucose – – – 2.23 0.06 – –
L-phenylalanine – – – 2.21 0.02 – –
3-hydroxybutyric acid V – – 2.20 2.90e-03 – –
9h-purine – – – 2.18 5.00e-03 – –
4-hydroxyphenylacetic acid – – – 2.10 0.02 – –
3-hydroxybutyric acid V – – 2.09 0.10 – –
uric acid V – – 2.08 0.18 – –
L-isoleucine – – – 2.07 7.00e-03 – –
5-oxoproline V – – 2.06 5.00e-03 – –
methionine V – – 2.05 0.01 – –
guanine – – – 2.02 0.01 – –
L-proline V – – 2.02 8.00e-03 – –
N-acetylaspartic acid – – – 2.01 9.00e-03 – –
thiodiglycolic acid – – – 1.97 9.00e-03 – –
inosine – – – 1.97 1.00e-03 – –
pyrimidine – – – 1.92 7.00e-03 – –
L-threonine – – – 1.89 0.02 – –
L-valine – – – 1.88 0.02 – –
uracil – – – 1.86 0.01 – –
fumaric acid V – – 1.86 2.00e-03 – –
glyoxylic acid – – – 1.85 0.06 – –
fumaric acid V – – 1.84 1.00e-04 – –
succinic acid – – – 1.84 6.00e-03 – –
malic acid V – – 1.84 3.00e-04 – –
butanoic acid – – – 1.82 0.04 – –
L-serine – – – 1.82 0.03 – –
glycine V – – 1.77 6.00e-03 – –
fumaric acid V – – 1.76 1.00e-04 – –
octanoic acid V – – 1.74 1.00e-04 – –
L-leucine – – – 1.74 0.02 – –
D-gluconic acid – – – 1.73 5.00e-03 – –
L-alanine – – – 1.70 7.00e-03 – –
adenosine – – – 1.69 0.04 – –
4-hydroxyproline V – – 1.68 0.06 – –
uric acid V – – 1.67 0.09 – –
2-hydroxybutyric acid – – – 1.64 0.02 – –
2-hydroxyisovaleric acid V – – 1.62 0.02 – –
fumaric acid V – – 1.61 1.00e-04 – –
ethanimidic acid – – – 1.60 7.00e-03 – –
DL-ornithine – – – 1.59 0.04 – –
aspartic acid V – – 1.59 0.02 – –
octanoic acid V – – 1.58 1.00e-04 – –
lactic acid V – – 1.56 1.00e-04 – –
malonic acid – – – 1.54 0.05 – –
lactic acid V – – 1.51 1.00e-04 – –
aconitic acid V – – 1.49 0.08 – –
benzoic acid V – – 1.48 1.00e-04 – –
3-hydroxybutyric acid V – – 1.48 0.42 – –
4-hydroxyphenyllactic acid – – – 1.48 0.04 – –
3-hydroxyisobutyric acid – – – 1.47 0.43 – –
2-hydroxyisovaleric acid V – – 1.47 9.10e-03 – –
malic acid V – – 1.43 0.03 – –
4-hydroxyproline V – – 1.43 0.03 – –
L-glycine V – – 1.42 0.34 – –
L-lysine – – – 1.42 0.10 – –
lactic acid V – – 1.42 1.00e-03 – –
oxalic acid – – – 1.41 0.05 – –
L-proline V – – 1.41 4.20e-03 – –
glycerol – – – 1.40 0.07 – –
L-glycine V – – 1.40 0.01 – –
2-hydroxyisovaleric acid V – – 1.40 0.11 – –
malic acid V – – 1.40 2.00e-04 – –
2-hydroxyisobutyric acid V – – 1.39 1.00e-04 – –
benzoic acid V – – 1.39 1.00e-04 – –
palmitoleic acid V – – 1.35 0.38 – –
L-proline V – – 1.35 0.10 – –
2-hydroxyisobutyric acid V – – 1.35 1.00e-04 – –
malic acid V – – 1.35 3.60e-03 – –
palmitoleic acid V – – 1.34 0.23 – –
L-proline V – – 1.34 1.50e-03 – –
glycolic acid – – – 1.33 0.01 – –
palmitoleic acid V – – 1.33 0.30 – –
4-hydroxyproline V – – 1.31 0.41 – –
malonic acid – – – 1.31 3.60e-03 – –
glucuronic lactone – – – 1.29 0.10 – –
L-glycine V – – 1.29 0.05 – –
2-hydroxyisobutyric acid V – – 1.29 1.20e-03 – –
L-isoleucine – – – 1.28 0.02 – –
L-threonine – – – 1.27 0.05 – –
glyoxylic acid – – – 1.27 0.16 – –
malonic acid – – – 1.27 0.07 – –
L-isoleucine – – – 1.26 4.20e-03 – –
L-isoleucine – – – 1.25 0.07 – –
sarcosine V – – 1.24 1.00e-04 – –
L-methionine V – – 1.24 0.21 – –
3-hydroxyisobutyric acid – – – 1.24 0.17 – –
L-threonine – – – 1.24 0.04 – –
4-hydroxyphenyllactic acid – – – 1.23 0.40 – –
octanoic acid V – – 1.23 0.04 – –
lactic acid V – – 1.22 0.02 – –
malonic acid – – – 1.22 0.01 – –
α-amino butyric acid – – – 1.22 0.14 – –
2-hydroxyisobutyric acid V – – 1.21 0.06 – –
benzoic acid V – – 1.21 0.01 – –
propanoic acid – – – 1.20 4.00e-03 – –
maleic acid – – – 1.20 0.16 – –
3-hydroxyisobutyric acid – – – 1.20 0.10 – –
glyoxylic acid – – – 1.19 0.19 – –
glucuronic lactone – – – 1.19 0.15 – –
3-hydroxyisobutyric acid – – – 1.18 0.38 – –
phosphoric acid V – – 1.18 1.00e-03 – –
oxalic acid – – – 1.18 0.25 – –
aconitic acid V – – 1.17 0.33 – –
L-methionine V – – 1.17 0.21 – –
sarcosine V – – 1.17 2.70e-03 – –
2-propyl-glutaric acid V – – 1.16 0.02 – –
2-hexenedioic acid V – – 1.16 8.00e-04 – –
L-threonine – – – 1.16 0.25 – –
glyoxylic acid – – – 1.15 0.62 – –
glucuronic lactone – – – 1.14 0.69 – –
L-methionine V – – 1.13 0.68 – –
L-alanine – – – 1.13 0.23 – –
maleic acid – – – 1.13 0.20 – –
2-propyl-glutaric acid V – – 1.13 0.02 – –
indol-3-acetic acid – – – 1.12 0.43 – –
3-hydroxypropionic acid – – – 1.11 0.80 – –
3-hydroxypropionic acid – – – 1.11 0.38 – –
2-hexenedioic acid V – – 1.11 0.02 – –
α-amino butyric acid – – – 1.10 0.36 – –
pyruvic acid V – – 1.10 0.27 – –
maleic acid – – – 1.09 0.77 – –
isovalerylglycine V – – 1.09 0.15 – –
citric acid – – – 1.09 0.48 – –
glucuronic lactone – – – 1.09 0.41 – –
2-propyl-glutaric acid V – – 1.09 0.10 – –
pyruvic acid V – – 1.08 0.46 – –
decanoic acid – – – 1.08 0.24 – –
L-glycine V – – 1.08 0.65 – –
3-hydroxypropionic acid – – – 1.08 0.37 – –
L-alanine – – – 1.08 0.32 – –
pyruvic acid V – – 1.08 0.18 – –
L-alanine – – – 1.07 0.79 – –
stearic acid – – – 1.07 0.03 – –
oxalic acid – – – 1.07 0.59 – –
7-hydroxyoctanoic acid – – – 1.07 0.37 – –
isovalerylglycine V – – 1.07 0.22 – –
3-hydroxypropionic acid – – – 1.06 0.80 – –
L-phenylalanine V – – 1.06 0.70 – –
L-valine – – – 1.06 0.58 – –
glucuronic lactone – – – 1.06 0.51 – –
glucuronic lactone – – – 1.05 0.83 – –
L-leucine – – – 1.05 0.67 – –
L-valine – – – 1.05 0.55 – –
glyceric acid V – – 1.04 0.89 – –
L-valine – – – 1.04 0.81 – –
α-amino butyric acid – – – 1.04 0.79 – –
L-leucine – – – 1.04 0.71 – –
L-leucine – – – 1.03 0.93 – –
isovalerylglycine V – – 1.03 0.71 – –
urea – – – 1.02 0.95 – –
oxalic acid – – – 1.02 0.76 – –
stearic acid – – – 1.02 0.49 – –
aconitic acid V – – 1.02 0.47 – –
isocitric acid – – – 1.02 0.90 – –
sarcosine V – – 1.02 0.87 – –
isocitric acid – – – 1.02 0.37 – –
citric acid – – – 1.01 0.98 – –
2-hexenedioic acid V – – 1.01 0.97 – –
decanoic acid – – – 1.01 0.95 – –
7-hydroxyoctanoic acid – – – 1.01 0.95 – –
urea – – – 1.00 0.92 – –
ethylmalonic acid – – – 1.00 0.95 – –
2-hydroxybutyric acid – – – 1.00 0.91 – –
margaric acid – – – 0.99 0.92 – –
ethylmalonic acid – – – 0.99 0.88 – –
ethylmalonic acid – – – 0.99 0.88 – –
urea – – – 0.99 0.55 – –
stearic acid – – – 0.99 0.54 – –
7-hydroxyoctanoic acid – – – 0.98 0.47 – –
glycolic acid – – – 0.98 0.85 – –
urea – – – 0.98 0.37 – –
pyruvic acid V – – 0.97 0.84 – –
palmitic acid – – – 0.97 0.54 – –
isocitric acid – – – 0.97 0.46 – –
citric acid – – – 0.97 0.44 – –
margaric acid – – – 0.97 0.49 – –
2-hydroxybutyric acid – – – 0.96 0.61 – –
2-hydroxybutyric acid – – – 0.95 0.53 – –
glycolic acid – – – 0.95 0.51 – –
margaric acid – – – 0.95 0.37 – –
succinic acid – – – 0.94 0.59 – –
glycolic acid – – – 0.94 0.47 – –
L-phenylalanine V – – 0.93 0.37 – –
stearic acid – – – 0.93 0.12 – –
succinic acid – – – 0.92 0.13 – –
L-serine – – – 0.91 0.33 – –
indol-3-acetic acid – – – 0.91 0.30 – –
glucuronic lactone – – – 0.90 0.74 – –
palmitic acid – – – 0.90 0.21 – –
L-serine – – – 0.90 0.13 – –
myristic acid – – – 0.89 0.34 – –
L-serine – – – 0.89 0.25 – –
5-oxoproline V – – 0.89 0.11 – –
palmitic acid – – – 0.89 0.07 – –
palmitic acid – – – 0.88 0.16 – –
decanoic acid – – – 0.88 0.25 – –
myristic acid – – – 0.88 0.09 – –
succinic acid – – – 0.88 0.08 – –
phosphoric acid V – – 0.87 0.11 – –
phosphoric acid V – – 0.87 0.01 – –
L-phenylalanine V – – 0.86 0.09 – –
myristic acid – – – 0.86 0.18 – –
phosphoric acid V – – 0.86 0.07 – –
5-oxoproline V – – 0.85 1.90e-03 – –
2-ketoglutaric acid – – – 0.84 0.32 – –
lauric acid – – – 0.83 0.51 – –
5-oxoproline V – – 0.83 6.20e-03 – –
L-glutamic acid V – – 0.83 0.37 – –
2-hydroxyphenylacetic acid – – – 0.80 0.06 – –
indol-3-acetic acid – – – 0.80 0.01 – –
glycerol – – – 0.79 0.21 – –
lauric acid – – – 0.77 0.04 – –
glycerol – – – 0.77 0.03 – –
glycerol – – – 0.74 0.09 – –
4-hydroxyphenyllactic acid – – – 0.73 0.10 – –
L-glutamic acid V – – 0.72 0.03 – –
myristic acid – – – 0.69 0.02 – –
aspartic acid V – – 0.68 0.05 – –
citric acid – – – 0.67 0.13 – –
isocitric acid – – – 0.67 0.12 – –
L-glutamic acid V – – 0.67 0.03 – –
aspartic acid V – – 0.65 3.00e-04 – –
lauric acid – – – 0.64 8.90e-03 – –
sarcosine V – – 0.62 0.37 – –
aspartic acid V – – 0.58 3.20e-03 – –
glyceric acid V – – 0.57 2.50e-03 – –
glyceric acid V – – 0.47 1.00e-04 – –
glyceric acid V – – 0.42 1.00e-04 – –
lauric acid – – – 0.39 1.00e-03 – –
margaric acid – – – 0.22 0.34 – –
Metabolite Author-emphasized biomarkers Cutoff value AUROC (95%CI) Sensitivity (%) Specificity (%) Accuracy (%)
L-tryptophan – – – – – –
L-cysteine – – – – – –
asparagine – – – – – –
4-hydroxyphenyllactic acid – – – – – –
uric acid V – – – – –
D-ribose – – – – – –
L-glutamine – – – – – –
L-tyrosine – – – – – –
3-hydroxybutyric acid V – – – – –
α-aminoadipic acid – – – – – –
uric acid V – – – – –
aminomalonic acid – – – – – –
N-acetyl glucosamine – – – – – –
L-glutamic acid V – – – – –
2-hydroxyglutaric acid – – – – – –
D-glucose – – – – – –
L-phenylalanine – – – – – –
3-hydroxybutyric acid V – – – – –
9h-purine – – – – – –
4-hydroxyphenylacetic acid – – – – – –
3-hydroxybutyric acid V – – – – –
uric acid V – – – – –
L-isoleucine – – – – – –
5-oxoproline V – – – – –
methionine V – – – – –
guanine – – – – – –
L-proline V – – – – –
N-acetylaspartic acid – – – – – –
thiodiglycolic acid – – – – – –
inosine – – – – – –
pyrimidine – – – – – –
L-threonine – – – – – –
L-valine – – – – – –
uracil – – – – – –
fumaric acid V – – – – –
glyoxylic acid – – – – – –
fumaric acid V – – – – –
succinic acid – – – – – –
malic acid V – – – – –
butanoic acid – – – – – –
L-serine – – – – – –
glycine V – – – – –
fumaric acid V – – – – –
octanoic acid V – – – – –
L-leucine – – – – – –
D-gluconic acid – – – – – –
L-alanine – – – – – –
adenosine – – – – – –
4-hydroxyproline V – – – – –
uric acid V – – – – –
2-hydroxybutyric acid – – – – – –
2-hydroxyisovaleric acid V – – – – –
fumaric acid V – – – – –
ethanimidic acid – – – – – –
DL-ornithine – – – – – –
aspartic acid V – – – – –
octanoic acid V – – – – –
lactic acid V – – – – –
malonic acid – – – – – –
lactic acid V – – – – –
aconitic acid V – – – – –
benzoic acid V – – – – –
3-hydroxybutyric acid V – – – – –
4-hydroxyphenyllactic acid – – – – – –
3-hydroxyisobutyric acid – – – – – –
2-hydroxyisovaleric acid V – – – – –
malic acid V – – – – –
4-hydroxyproline V – – – – –
L-glycine V – – – – –
L-lysine – – – – – –
lactic acid V – – – – –
oxalic acid – – – – – –
L-proline V – – – – –
glycerol – – – – – –
L-glycine V – – – – –
2-hydroxyisovaleric acid V – – – – –
malic acid V – – – – –
2-hydroxyisobutyric acid V – – – – –
benzoic acid V – – – – –
palmitoleic acid V – – – – –
L-proline V – – – – –
2-hydroxyisobutyric acid V – – – – –
malic acid V – – – – –
palmitoleic acid V – – – – –
L-proline V – – – – –
glycolic acid – – – – – –
palmitoleic acid V – – – – –
4-hydroxyproline V – – – – –
malonic acid – – – – – –
glucuronic lactone – – – – – –
L-glycine V – – – – –
2-hydroxyisobutyric acid V – – – – –
L-isoleucine – – – – – –
L-threonine – – – – – –
glyoxylic acid – – – – – –
malonic acid – – – – – –
L-isoleucine – – – – – –
L-isoleucine – – – – – –
sarcosine V – – – – –
L-methionine V – – – – –
3-hydroxyisobutyric acid – – – – – –
L-threonine – – – – – –
4-hydroxyphenyllactic acid – – – – – –
octanoic acid V – – – – –
lactic acid V – – – – –
malonic acid – – – – – –
α-amino butyric acid – – – – – –
2-hydroxyisobutyric acid V – – – – –
benzoic acid V – – – – –
propanoic acid – – – – – –
maleic acid – – – – – –
3-hydroxyisobutyric acid – – – – – –
glyoxylic acid – – – – – –
glucuronic lactone – – – – – –
3-hydroxyisobutyric acid – – – – – –
phosphoric acid V – – – – –
oxalic acid – – – – – –
aconitic acid V – – – – –
L-methionine V – – – – –
sarcosine V – – – – –
2-propyl-glutaric acid V – – – – –
2-hexenedioic acid V – – – – –
L-threonine – – – – – –
glyoxylic acid – – – – – –
glucuronic lactone – – – – – –
L-methionine V – – – – –
L-alanine – – – – – –
maleic acid – – – – – –
2-propyl-glutaric acid V – – – – –
indol-3-acetic acid – – – – – –
3-hydroxypropionic acid – – – – – –
3-hydroxypropionic acid – – – – – –
2-hexenedioic acid V – – – – –
α-amino butyric acid – – – – – –
pyruvic acid V – – – – –
maleic acid – – – – – –
isovalerylglycine V – – – – –
citric acid – – – – – –
glucuronic lactone – – – – – –
2-propyl-glutaric acid V – – – – –
pyruvic acid V – – – – –
decanoic acid – – – – – –
L-glycine V – – – – –
3-hydroxypropionic acid – – – – – –
L-alanine – – – – – –
pyruvic acid V – – – – –
L-alanine – – – – – –
stearic acid – – – – – –
oxalic acid – – – – – –
7-hydroxyoctanoic acid – – – – – –
isovalerylglycine V – – – – –
3-hydroxypropionic acid – – – – – –
L-phenylalanine V – – – – –
L-valine – – – – – –
glucuronic lactone – – – – – –
glucuronic lactone – – – – – –
L-leucine – – – – – –
L-valine – – – – – –
glyceric acid V – – – – –
L-valine – – – – – –
α-amino butyric acid – – – – – –
L-leucine – – – – – –
L-leucine – – – – – –
isovalerylglycine V – – – – –
urea – – – – – –
oxalic acid – – – – – –
stearic acid – – – – – –
aconitic acid V – – – – –
isocitric acid – – – – – –
sarcosine V – – – – –
isocitric acid – – – – – –
citric acid – – – – – –
2-hexenedioic acid V – – – – –
decanoic acid – – – – – –
7-hydroxyoctanoic acid – – – – – –
urea – – – – – –
ethylmalonic acid – – – – – –
2-hydroxybutyric acid – – – – – –
margaric acid – – – – – –
ethylmalonic acid – – – – – –
ethylmalonic acid – – – – – –
urea – – – – – –
stearic acid – – – – – –
7-hydroxyoctanoic acid – – – – – –
glycolic acid – – – – – –
urea – – – – – –
pyruvic acid V – – – – –
palmitic acid – – – – – –
isocitric acid – – – – – –
citric acid – – – – – –
margaric acid – – – – – –
2-hydroxybutyric acid – – – – – –
2-hydroxybutyric acid – – – – – –
glycolic acid – – – – – –
margaric acid – – – – – –
succinic acid – – – – – –
glycolic acid – – – – – –
L-phenylalanine V – – – – –
stearic acid – – – – – –
succinic acid – – – – – –
L-serine – – – – – –
indol-3-acetic acid – – – – – –
glucuronic lactone – – – – – –
palmitic acid – – – – – –
L-serine – – – – – –
myristic acid – – – – – –
L-serine – – – – – –
5-oxoproline V – – – – –
palmitic acid – – – – – –
palmitic acid – – – – – –
decanoic acid – – – – – –
myristic acid – – – – – –
succinic acid – – – – – –
phosphoric acid V – – – – –
phosphoric acid V – – – – –
L-phenylalanine V – – – – –
myristic acid – – – – – –
phosphoric acid V – – – – –
5-oxoproline V – – – – –
2-ketoglutaric acid – – – – – –
lauric acid – – – – – –
5-oxoproline V – – – – –
L-glutamic acid V – – – – –
2-hydroxyphenylacetic acid – – – – – –
indol-3-acetic acid – – – – – –
glycerol – – – – – –
lauric acid – – – – – –
glycerol – – – – – –
glycerol – – – – – –
4-hydroxyphenyllactic acid – – – – – –
L-glutamic acid V – – – – –
myristic acid – – – – – –
aspartic acid V – – – – –
citric acid – – – – – –
isocitric acid – – – – – –
L-glutamic acid V – – – – –
aspartic acid V – – – – –
lauric acid – – – – – –
sarcosine V – – – – –
aspartic acid V – – – – –
glyceric acid V – – – – –
glyceric acid V – – – – –
glyceric acid V – – – – –
lauric acid – – – – – –
margaric acid – – – – – –

Paper graphical summary