title: Discovery and Validation of Predictive Biomarkers of Survival for Non-small Cell Lung Cancer Patients Undergoing Radical Radiotherapy: Two Proteins With Predictive Value.
abstract: Lung cancer is the most frequent cause of cancer-related death world-wide. Radiotherapy alone or in conjunction with chemotherapy is the standard treatment for locally advanced non-small cell lung cancer (NSCLC). Currently there is no predictive marker with clinical utility to guide treatment decisions in NSCLC patients undergoing radiotherapy. Identification of such markers would allow treatment options to be considered for more effective therapy. To enable the identification of appropriate protein biomarkers, plasma samples were collected from patients with non-small cell lung cancer before and during radiotherapy for longitudinal comparison following a protocol that carries sufficient power for effective discovery proteomics. Plasma samples from patients pre- and during radiotherapy who had survived > 18 mo were compared to the same time points from patients who survived < 14 mo using an 8 channel isobaric tagging tandem mass spectrometry discovery proteomics platform. Over 650 proteins were detected and relatively quantified. Proteins which showed a change during radiotherapy were selected for validation using an orthogonal antibody-based approach. Two of these proteins were verified in a separate patient cohort: values of CRP and LRG1 combined gave a highly significant indication of extended survival post one week of radiotherapy treatment.
authors.affiliation: Stoller Biomarker Discovery Centre, Manchester Academic Health Science Centre, The University of Manchester, Wolfson Molecular Imaging Centre, Manchester M20 3LJ, UK.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Walker
authors.affiliation: Stoller Biomarker Discovery Centre, Manchester Academic Health Science Centre, The University of Manchester, Wolfson Molecular Imaging Centre, Manchester M20 3LJ, UK ; Clinical and Experimental Pharmacology Group, Cancer Research UK Manchester Institute, Manchester Academic Health Science Centre, Christie Hospital, University of Manchester, Manchester M20 4BX, UK.
authors.forename: Cong
authors.initials: C
authors.lastname: Zhou
authors.affiliation: Clinical and Experimental Pharmacology Group, Cancer Research UK Manchester Institute, Manchester Academic Health Science Centre, Christie Hospital, University of Manchester, Manchester M20 4BX, UK.
authors.forename: Alison
authors.initials: A
authors.lastname: Backen
authors.affiliation: Stoller Biomarker Discovery Centre, Manchester Academic Health Science Centre, The University of Manchester, Wolfson Molecular Imaging Centre, Manchester M20 3LJ, UK ; Karolinska Institutet, Scilifelab, Department of Oncology and Pathology, Tomtebodavägen 23, 171 65 Stockholm, Sweden.
authors.forename: Maria
authors.initials: M
authors.lastname: Pernemalm
authors.affiliation: Stoller Biomarker Discovery Centre, Manchester Academic Health Science Centre, The University of Manchester, Wolfson Molecular Imaging Centre, Manchester M20 3LJ, UK.
authors.forename: Andrew J K
authors.initials: AJ
authors.lastname: Williamson
authors.affiliation: Clinical and Experimental Pharmacology Group, Cancer Research UK Manchester Institute, Manchester Academic Health Science Centre, Christie Hospital, University of Manchester, Manchester M20 4BX, UK ; Faculty Institute of Cancer Sciences, Manchester Academic Health Sciences Centre, University of Manchester, M20 4BX, UK.
authors.forename: Lynsey J C
authors.initials: LJ
authors.lastname: Priest
authors.affiliation: Faculty Institute of Cancer Sciences, Manchester Academic Health Sciences Centre, University of Manchester, M20 4BX, UK.
authors.forename: Pek
authors.initials: P
authors.lastname: Koh
authors.affiliation: Faculty Institute of Cancer Sciences, Manchester Academic Health Sciences Centre, University of Manchester, M20 4BX, UK ; The Christie NHS Foundation Trust, Wilmslow Road, Manchester M20 4BX, UK.
authors.forename: Corinne
authors.initials: C
authors.lastname: Faivre-Finn
authors.affiliation: Faculty Institute of Cancer Sciences, Manchester Academic Health Sciences Centre, University of Manchester, M20 4BX, UK ; The Christie NHS Foundation Trust, Wilmslow Road, Manchester M20 4BX, UK.
authors.forename: Fiona H
authors.initials: FH
authors.lastname: Blackhall
authors.affiliation: Clinical and Experimental Pharmacology Group, Cancer Research UK Manchester Institute, Manchester Academic Health Science Centre, Christie Hospital, University of Manchester, Manchester M20 4BX, UK.
authors.forename: Caroline
authors.initials: C
authors.lastname: Dive
authors.affiliation: Stoller Biomarker Discovery Centre, Manchester Academic Health Science Centre, The University of Manchester, Wolfson Molecular Imaging Centre, Manchester M20 3LJ, UK.
authors.forename: Anthony D
authors.initials: AD
authors.lastname: Whetton
mesh_terms: D014408:Biomarkers, Tumor / Q000097:blood*; D002097:C-Reactive Protein / Q000378:metabolism*; D002289:Carcinoma, Non-Small-Cell Lung / Q000097:blood / Q000401:mortality / Q000532:radiotherapy; D015331:Cohort Studies; D018572:Disease-Free Survival; D005260:Female; D006023:Glycoproteins / Q000097:blood*; D006801:Humans; D008175:Lung Neoplasms / Q000097:blood / Q000401:mortality / Q000532:radiotherapy; D008297:Male; D009363:Neoplasm Proteins / Q000097:blood*; D015996:Survival Rate
chemical_list: D014408:Biomarkers, Tumor; D006023:Glycoproteins; C015246:LRG1 protein, human; D009363:Neoplasm Proteins; D002097:C-Reactive Protein
keywords: AC, adenocarcinoma; Biomarker; CEA, carcinoembryonic antigen; CRP, C-reactive protein; EGFR, epidermal growth factor receptor; FDR, false discovery rate; IL-6, Interleukin 6; LBP, lipopolysaccharide binding protein; LRG1, leucine-rich alpha-2-glycoprotein; Lung cancer; MS/MS, tandem mass spectrometry; NSCLC, non-small cell lung cancer; PCA, principal component analysis; Proteomics; Radiotherapy; SCLC, small cell lung cancer; SqCC, squamous cell carcinoma; TEAB, triethyl ammonium bicarbonate; VEGF, vascular endothelial growth factor; iTRAQ, isobaric tagging for relative and absolute quantification; mo, months; v/v, volume/volume