title: Proteomic biomarkers for acute interstitial lung disease in gefitinib-treated Japanese lung cancer patients.
abstract: Interstitial lung disease (ILD) events have been reported in Japanese non-small-cell lung cancer (NSCLC) patients receiving EGFR tyrosine kinase inhibitors. We investigated proteomic biomarkers for mechanistic insights and improved prediction of ILD. Blood plasma was collected from 43 gefitinib-treated NSCLC patients developing acute ILD (confirmed by blinded diagnostic review) and 123 randomly selected controls in a nested case-control study within a pharmacoepidemiological cohort study in Japan. We generated ∼7 million tandem mass spectrometry (MS/MS) measurements with extensive quality control and validation, producing one of the largest proteomic lung cancer datasets to date, incorporating rigorous study design, phenotype definition, and evaluation of sample processing. After alignment, scaling, and measurement batch adjustment, we identified 41 peptide peaks representing 29 proteins best predicting ILD. Multivariate peptide, protein, and pathway modeling achieved ILD prediction comparable to previously identified clinical variables; combining the two provided some improvement. The acute phase response pathway was strongly represented (17 of 29 proteins, p = 1.0×10(-25)), suggesting a key role with potential utility as a marker for increased risk of acute ILD events. Validation by Western blotting showed correlation for identified proteins, confirming that robust results can be generated from an MS/MS platform implementing strict quality control.
authors.affiliation: Global Epidemiology, AstraZeneca R&D, Mölndal, Sweden. Fredrik.Nyberg@astrazeneca.com
authors.forename: Fredrik
authors.initials: F
authors.lastname: Nyberg
authors.forename: Atsushi
authors.initials: A
authors.lastname: Ogiwara
authors.forename: Chris G
authors.initials: CG
authors.lastname: Harbron
authors.forename: Takao
authors.initials: T
authors.lastname: Kawakami
authors.forename: Keiko
authors.initials: K
authors.lastname: Nagasaka
authors.forename: Sachiko
authors.initials: S
authors.lastname: Takami
authors.forename: Kazuya
authors.initials: K
authors.lastname: Wada
authors.forename: Hsiao-Kun
authors.initials: HK
authors.lastname: Tu
authors.forename: Makiko
authors.initials: M
authors.lastname: Otsuji
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Kyono
authors.forename: Tae
authors.initials: T
authors.lastname: Dobashi
authors.forename: Yasuhiko
authors.initials: Y
authors.lastname: Komatsu
authors.forename: Makoto
authors.initials: M
authors.lastname: Kihara
authors.forename: Shingo
authors.initials: S
authors.lastname: Akimoto
authors.forename: Ian S
authors.initials: IS
authors.lastname: Peers
authors.forename: Marie C
authors.initials: MC
authors.lastname: South
authors.forename: Tim
authors.initials: T
authors.lastname: Higenbottam
authors.forename: Masahiro
authors.initials: M
authors.lastname: Fukuoka
authors.forename: Koichiro
authors.initials: K
authors.lastname: Nakata
authors.forename: Yuichiro
authors.initials: Y
authors.lastname: Ohe
authors.forename: Shoji
authors.initials: S
authors.lastname: Kudoh
authors.forename: Ib Groth
authors.initials: IG
authors.lastname: Clausen
authors.forename: Toshihide
authors.initials: T
authors.lastname: Nishimura
authors.forename: György
authors.initials: G
authors.lastname: Marko-Varga
authors.forename: Harubumi
authors.initials: H
authors.lastname: Kato
mesh_terms: D044466:Asian People; D015415:Biomarkers / Q000097:blood; D002289:Carcinoma, Non-Small-Cell Lung / Q000150:complications / Q000188:drug therapy; D002853:Chromatography, Liquid; D030562:Databases, Protein; D016002:Discriminant Analysis; D000077156:Gefitinib; D006801:Humans; D017563:Lung Diseases, Interstitial / Q000097:blood* / Q000150:complications* / Q000175:diagnosis; D008175:Lung Neoplasms / Q000150:complications* / Q000188:drug therapy*; D010455:Peptides / Q000097:blood / Q000302:isolation & purification; D010641:Phenotype; D040901:Proteomics / Q000379:methods*; D011786:Quality Control; D011799:Quinazolines / Q000627:therapeutic use*; D015203:Reproducibility of Results; D053719:Tandem Mass Spectrometry
chemical_list: D015415:Biomarkers; D010455:Peptides; D011799:Quinazolines; D000077156:Gefitinib