Blood-based lung cancer biomarkers identified through proteomic discovery in cancer tissues, cell lines and conditioned medium

Charles E. Birse, Robert J. Lagier, William FitzHugh, Harvey I. Pass, William N. Rom, Eric Edell, Aaron O. Bungum, Fabien Maldonado, James R. Jett, Mehdi Mesri, Erin Sult, Elizabeth Joseloff, Aiqun Li, Jenny Heidbrink, Gulshan Dhariwal, Chad Danis, Jennifer L. Tomic, Robert J. Bruce, Paul A. Moore, Tao He & 2 others Marcia E. Lewis, Steve M. Ruben

Research output: Contribution to journalArticle

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Abstract

Background: Support for early detection of lung cancer has emerged from the National Lung Screening Trial (NLST), in which low-dose computed tomography (LDCT) screening reduced lung cancer mortality by 20 % relative to chest x-ray. The US Preventive Services Task Force (USPSTF) recently recommended annual screening for the high-risk population, concluding that the benefits (life years gained) outweighed harms (false positive findings, abortive biopsy/surgery, radiation exposure). In making their recommendation, the USPSTF noted that the moderate net benefit of screening was dependent on the resolution of most false-positive results without invasive procedures. Circulating biomarkers may serve as a valuable adjunctive tool to imaging. Results: We developed a broad-based proteomics discovery program, integrating liquid chromatography/mass spectrometry (LC/MS) analyses of freshly resected lung tumor specimens (n = 13), lung cancer cell lines (n = 17), and conditioned media collected from tumor cell lines (n = 7). To enrich for biomarkers likely to be found at elevated levels in the peripheral circulation of lung cancer patients, proteins were prioritized based on predicted subcellular localization (secreted, cell-membrane associated) and differential expression in disease samples. 179 candidate biomarkers were identified. Several markers selected for further validation showed elevated levels in serum collected from subjects with stage I NSCLC (n = 94), relative to healthy smoker controls (n = 189). An 8-marker model was developed (TFPI, MDK, OPN, MMP2, TIMP1, CEA, CYFRA 21-1, SCC) which accurately distinguished subjects with lung cancer (n = 50) from high risk smokers (n = 50) in an independent validation study (AUC = 0.775). Conclusions: Integrating biomarker discovery from multiple sample types (fresh tissue, cell lines and conditioned medium) has resulted in a diverse repertoire of candidate biomarkers. This unique collection of biomarkers may have clinical utility in lung cancer detection and diagnoses.

Original languageEnglish (US)
Article number18
JournalClinical Proteomics
Volume12
Issue number1
DOIs
StatePublished - Jul 16 2015

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Biomarkers
Tumor Biomarkers
Conditioned Culture Medium
Proteomics
Lung Neoplasms
Blood
Cells
Tissue
Cell Line
Screening
Neoplasms
Advisory Committees
Tumors
Lung
Biopsy
Validation Studies
Liquid chromatography
Cell membranes
Tumor Cell Line
Early Detection of Cancer

Keywords

  • Biomarker
  • Discovery
  • Early detection
  • Lung cancer
  • Mass spectrometry
  • Proteomics

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Clinical Biochemistry

Cite this

Blood-based lung cancer biomarkers identified through proteomic discovery in cancer tissues, cell lines and conditioned medium. / Birse, Charles E.; Lagier, Robert J.; FitzHugh, William; Pass, Harvey I.; Rom, William N.; Edell, Eric; Bungum, Aaron O.; Maldonado, Fabien; Jett, James R.; Mesri, Mehdi; Sult, Erin; Joseloff, Elizabeth; Li, Aiqun; Heidbrink, Jenny; Dhariwal, Gulshan; Danis, Chad; Tomic, Jennifer L.; Bruce, Robert J.; Moore, Paul A.; He, Tao; Lewis, Marcia E.; Ruben, Steve M.

In: Clinical Proteomics, Vol. 12, No. 1, 18, 16.07.2015.

Research output: Contribution to journalArticle

Birse, CE, Lagier, RJ, FitzHugh, W, Pass, HI, Rom, WN, Edell, E, Bungum, AO, Maldonado, F, Jett, JR, Mesri, M, Sult, E, Joseloff, E, Li, A, Heidbrink, J, Dhariwal, G, Danis, C, Tomic, JL, Bruce, RJ, Moore, PA, He, T, Lewis, ME & Ruben, SM 2015, 'Blood-based lung cancer biomarkers identified through proteomic discovery in cancer tissues, cell lines and conditioned medium', Clinical Proteomics, vol. 12, no. 1, 18. https://doi.org/10.1186/s12014-015-9090-9
Birse, Charles E. ; Lagier, Robert J. ; FitzHugh, William ; Pass, Harvey I. ; Rom, William N. ; Edell, Eric ; Bungum, Aaron O. ; Maldonado, Fabien ; Jett, James R. ; Mesri, Mehdi ; Sult, Erin ; Joseloff, Elizabeth ; Li, Aiqun ; Heidbrink, Jenny ; Dhariwal, Gulshan ; Danis, Chad ; Tomic, Jennifer L. ; Bruce, Robert J. ; Moore, Paul A. ; He, Tao ; Lewis, Marcia E. ; Ruben, Steve M. / Blood-based lung cancer biomarkers identified through proteomic discovery in cancer tissues, cell lines and conditioned medium. In: Clinical Proteomics. 2015 ; Vol. 12, No. 1.
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AU - Birse, Charles E.

AU - Lagier, Robert J.

AU - FitzHugh, William

AU - Pass, Harvey I.

AU - Rom, William N.

AU - Edell, Eric

AU - Bungum, Aaron O.

AU - Maldonado, Fabien

AU - Jett, James R.

AU - Mesri, Mehdi

AU - Sult, Erin

AU - Joseloff, Elizabeth

AU - Li, Aiqun

AU - Heidbrink, Jenny

AU - Dhariwal, Gulshan

AU - Danis, Chad

AU - Tomic, Jennifer L.

AU - Bruce, Robert J.

AU - Moore, Paul A.

AU - He, Tao

AU - Lewis, Marcia E.

AU - Ruben, Steve M.

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N2 - Background: Support for early detection of lung cancer has emerged from the National Lung Screening Trial (NLST), in which low-dose computed tomography (LDCT) screening reduced lung cancer mortality by 20 % relative to chest x-ray. The US Preventive Services Task Force (USPSTF) recently recommended annual screening for the high-risk population, concluding that the benefits (life years gained) outweighed harms (false positive findings, abortive biopsy/surgery, radiation exposure). In making their recommendation, the USPSTF noted that the moderate net benefit of screening was dependent on the resolution of most false-positive results without invasive procedures. Circulating biomarkers may serve as a valuable adjunctive tool to imaging. Results: We developed a broad-based proteomics discovery program, integrating liquid chromatography/mass spectrometry (LC/MS) analyses of freshly resected lung tumor specimens (n = 13), lung cancer cell lines (n = 17), and conditioned media collected from tumor cell lines (n = 7). To enrich for biomarkers likely to be found at elevated levels in the peripheral circulation of lung cancer patients, proteins were prioritized based on predicted subcellular localization (secreted, cell-membrane associated) and differential expression in disease samples. 179 candidate biomarkers were identified. Several markers selected for further validation showed elevated levels in serum collected from subjects with stage I NSCLC (n = 94), relative to healthy smoker controls (n = 189). An 8-marker model was developed (TFPI, MDK, OPN, MMP2, TIMP1, CEA, CYFRA 21-1, SCC) which accurately distinguished subjects with lung cancer (n = 50) from high risk smokers (n = 50) in an independent validation study (AUC = 0.775). Conclusions: Integrating biomarker discovery from multiple sample types (fresh tissue, cell lines and conditioned medium) has resulted in a diverse repertoire of candidate biomarkers. This unique collection of biomarkers may have clinical utility in lung cancer detection and diagnoses.

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KW - Mass spectrometry

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