Noninvasive urinary metabolomic profiling identifies diagnostic and prognostic markers in lung cancer

Ewy A. Mathé, Andrew David Patterson, Majda Haznadar, Soumen K. Manna, Kristopher W. Krausz, Elise D. Bowman, Peter G. Shields, Jeffrey R. Idle, Philip B. Smith, Katsuhiro Anami, Dickran G. Kazandjian, Emmanuel Hatzakis, Frank J. Gonzalez, Curtis C. Harris

Research output: Contribution to journalArticle

60 Citations (Scopus)

Abstract

Lung cancer remains the most common cause of cancer deaths worldwide, yet there is currently a lack of diagnostic noninvasive biomarkers that could guide treatment decisions. Small molecules (<1,500 Da) were measured in urine collected from 469 patients with lung cancer and 536 population controls using unbiased liquid chromatography/mass spectrometry. Clinical putative diagnostic and prognostic biomarkers were validated by quantitation and normalized to creatinine levels at two different time points and further confirmed in an independent sample set, which comprises 80 cases and 78 population controls, with similar demographic and clinical characteristics when compared with the training set. Creatine riboside (IUPAC name: 2-{2-[(2R,3R,4S,5R)-3,4-dihydroxy- 5-(hydroxymethyl)-oxolan-2-yl]-1-methylcarbamimidamido}acetic acid), a novel molecule identified in this study, and N-acetylneuraminic acid (NANA) were each significantly (P < 0.00001) elevated in non-small cell lung cancer and associated with worse prognosis [HR = 1.81 (P = 0.0002), and 1.54 (P = 0.025), respectively]. Creatine riboside was the strongest classi fier of lung cancer status in all and stage I-II cases, important for early detection, and also associated with worse prognosis in stage I-II lung cancer (HR = 1.71, P = 0.048). All measurements were highly reproducible with intraclass correlation coefficients ranging from 0.82 to 0.99. Both metabolites were significantly (P < 0.03) enriched in tumor tissue compared with adjacent nontumor tissue (N = 48), thus revealing their direct association with tumor metabolism. Creatine riboside and NANA may be robust urinary clinical metabolomic markers that are elevated in tumor tissue and associated with early lung cancer diagnosis and worse prognosis.

Original languageEnglish (US)
Pages (from-to)3259-3270
Number of pages12
JournalCancer Research
Volume74
Issue number12
DOIs
StatePublished - Jun 15 2014

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Metabolomics
Lung Neoplasms
Population Control
Biomarkers
N-Acetylneuraminic Acid
Neoplasms
Early Detection of Cancer
Non-Small Cell Lung Carcinoma
Liquid Chromatography
Acetic Acid
Names
Cause of Death
Mass Spectrometry
Creatinine
Demography
Urine
2-(2-(3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl)-1-methylcarbamimidamido)acetic acid

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Cite this

Mathé, E. A., Patterson, A. D., Haznadar, M., Manna, S. K., Krausz, K. W., Bowman, E. D., ... Harris, C. C. (2014). Noninvasive urinary metabolomic profiling identifies diagnostic and prognostic markers in lung cancer. Cancer Research, 74(12), 3259-3270. https://doi.org/10.1158/0008-5472.CAN-14-0109
Mathé, Ewy A. ; Patterson, Andrew David ; Haznadar, Majda ; Manna, Soumen K. ; Krausz, Kristopher W. ; Bowman, Elise D. ; Shields, Peter G. ; Idle, Jeffrey R. ; Smith, Philip B. ; Anami, Katsuhiro ; Kazandjian, Dickran G. ; Hatzakis, Emmanuel ; Gonzalez, Frank J. ; Harris, Curtis C. / Noninvasive urinary metabolomic profiling identifies diagnostic and prognostic markers in lung cancer. In: Cancer Research. 2014 ; Vol. 74, No. 12. pp. 3259-3270.
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abstract = "Lung cancer remains the most common cause of cancer deaths worldwide, yet there is currently a lack of diagnostic noninvasive biomarkers that could guide treatment decisions. Small molecules (<1,500 Da) were measured in urine collected from 469 patients with lung cancer and 536 population controls using unbiased liquid chromatography/mass spectrometry. Clinical putative diagnostic and prognostic biomarkers were validated by quantitation and normalized to creatinine levels at two different time points and further confirmed in an independent sample set, which comprises 80 cases and 78 population controls, with similar demographic and clinical characteristics when compared with the training set. Creatine riboside (IUPAC name: 2-{2-[(2R,3R,4S,5R)-3,4-dihydroxy- 5-(hydroxymethyl)-oxolan-2-yl]-1-methylcarbamimidamido}acetic acid), a novel molecule identified in this study, and N-acetylneuraminic acid (NANA) were each significantly (P < 0.00001) elevated in non-small cell lung cancer and associated with worse prognosis [HR = 1.81 (P = 0.0002), and 1.54 (P = 0.025), respectively]. Creatine riboside was the strongest classi fier of lung cancer status in all and stage I-II cases, important for early detection, and also associated with worse prognosis in stage I-II lung cancer (HR = 1.71, P = 0.048). All measurements were highly reproducible with intraclass correlation coefficients ranging from 0.82 to 0.99. Both metabolites were significantly (P < 0.03) enriched in tumor tissue compared with adjacent nontumor tissue (N = 48), thus revealing their direct association with tumor metabolism. Creatine riboside and NANA may be robust urinary clinical metabolomic markers that are elevated in tumor tissue and associated with early lung cancer diagnosis and worse prognosis.",
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Mathé, EA, Patterson, AD, Haznadar, M, Manna, SK, Krausz, KW, Bowman, ED, Shields, PG, Idle, JR, Smith, PB, Anami, K, Kazandjian, DG, Hatzakis, E, Gonzalez, FJ & Harris, CC 2014, 'Noninvasive urinary metabolomic profiling identifies diagnostic and prognostic markers in lung cancer', Cancer Research, vol. 74, no. 12, pp. 3259-3270. https://doi.org/10.1158/0008-5472.CAN-14-0109

Noninvasive urinary metabolomic profiling identifies diagnostic and prognostic markers in lung cancer. / Mathé, Ewy A.; Patterson, Andrew David; Haznadar, Majda; Manna, Soumen K.; Krausz, Kristopher W.; Bowman, Elise D.; Shields, Peter G.; Idle, Jeffrey R.; Smith, Philip B.; Anami, Katsuhiro; Kazandjian, Dickran G.; Hatzakis, Emmanuel; Gonzalez, Frank J.; Harris, Curtis C.

In: Cancer Research, Vol. 74, No. 12, 15.06.2014, p. 3259-3270.

Research output: Contribution to journalArticle

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T1 - Noninvasive urinary metabolomic profiling identifies diagnostic and prognostic markers in lung cancer

AU - Mathé, Ewy A.

AU - Patterson, Andrew David

AU - Haznadar, Majda

AU - Manna, Soumen K.

AU - Krausz, Kristopher W.

AU - Bowman, Elise D.

AU - Shields, Peter G.

AU - Idle, Jeffrey R.

AU - Smith, Philip B.

AU - Anami, Katsuhiro

AU - Kazandjian, Dickran G.

AU - Hatzakis, Emmanuel

AU - Gonzalez, Frank J.

AU - Harris, Curtis C.

PY - 2014/6/15

Y1 - 2014/6/15

N2 - Lung cancer remains the most common cause of cancer deaths worldwide, yet there is currently a lack of diagnostic noninvasive biomarkers that could guide treatment decisions. Small molecules (<1,500 Da) were measured in urine collected from 469 patients with lung cancer and 536 population controls using unbiased liquid chromatography/mass spectrometry. Clinical putative diagnostic and prognostic biomarkers were validated by quantitation and normalized to creatinine levels at two different time points and further confirmed in an independent sample set, which comprises 80 cases and 78 population controls, with similar demographic and clinical characteristics when compared with the training set. Creatine riboside (IUPAC name: 2-{2-[(2R,3R,4S,5R)-3,4-dihydroxy- 5-(hydroxymethyl)-oxolan-2-yl]-1-methylcarbamimidamido}acetic acid), a novel molecule identified in this study, and N-acetylneuraminic acid (NANA) were each significantly (P < 0.00001) elevated in non-small cell lung cancer and associated with worse prognosis [HR = 1.81 (P = 0.0002), and 1.54 (P = 0.025), respectively]. Creatine riboside was the strongest classi fier of lung cancer status in all and stage I-II cases, important for early detection, and also associated with worse prognosis in stage I-II lung cancer (HR = 1.71, P = 0.048). All measurements were highly reproducible with intraclass correlation coefficients ranging from 0.82 to 0.99. Both metabolites were significantly (P < 0.03) enriched in tumor tissue compared with adjacent nontumor tissue (N = 48), thus revealing their direct association with tumor metabolism. Creatine riboside and NANA may be robust urinary clinical metabolomic markers that are elevated in tumor tissue and associated with early lung cancer diagnosis and worse prognosis.

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