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Proteomic biomarkers for acute interstitial lung disease in gefitinib-treated Japanese lung cancer patients.

Nyberg F, Ogiwara A, Harbron CG, Kawakami T, Nagasaka K, Takami S, Wada K, Tu HK, Otsuji M, Kyono Y, Dobashi T, Komatsu Y, Kihara M, Akimoto S, Peers IS, South MC, Higenbottam T, Fukuoka M, Nakata K, Ohe Y, Kudoh S, Clausen IG, Nishimura T, Marko-Varga G, Kato H - PLoS ONE (2011)

Bottom Line: After alignment, scaling, and measurement batch adjustment, we identified 41 peptide peaks representing 29 proteins best predicting ILD.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.

View Article: PubMed Central - PubMed

Affiliation: Global Epidemiology, AstraZeneca R&D, Mölndal, Sweden. Fredrik.Nyberg@astrazeneca.com

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.

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Related in: MedlinePlus

Highest scoring Ingenuity Pathway Analysis network.Highest scoring network generated from entering the identified 29 proteins into the Ingenuity Pathway Analysis system, with proteins identified in the study shaded grey and connecting proteins identified by Ingenuity Pathway Analysis non-shaded. Dark blue shapes and lines  =  proteins identified as predictors in this study and interactions between them. Grey shapes and lines  =  proteins identified by Ingenuity to generate the network and interactions between them. Light blue lines  =  interactions between proteins identified by Ingenuity to generate the network and the proteins identified in the study. Figure S4A shows this figure with the interaction relationships labeled. Proteins identified in the study and included in the network: SERPINA1  =  alpha-1-antitrypsin; SERPINA3  =  alpha-1-antichymotrypsin; SERPINC1  =  antithrombin-III; APOA1  =  apolipoprotein A-I; APOB  =  apolipoprotein B-100; APOC3  =  apolipoprotein C-III; C3  =  complement C3; C4A, C4B  =  complement C4-A; complement C4-B; C9  =  complement component C9; GSN  =  gelsolin; HBA2  =  hemoglobin alpha; HBB, HBD  =  hemoglobin beta/delta; HP  =  haptoglobin; HPR  =  haptoglobin-related protein; HRG  =  histidine-rich glycoprotein; KLKB1  =  plasma kallikrein; IGKC  =  Ig kappa chain V-III region Ti; RBP4, Rbp  =  retinol binding protein 4; APCS  =  serum amyloid P-component; TF  =  serotransferrin; TTR  =  transthyretin. Proteins identified in the study and not included in the network: ORM1  =  alpha-1-acid glycoprotein 1; A1BG  =  alpha-1B-glycoprotein; LRG1  =  leucine-rich alpha-2-glycoprotein; ARMC2  =  armadillo repeat-containing protein 2; AHSG  =  alpha-2-HS-glycoprotein; ITIH4  =  inter-alpha-trypsin inhibitor heavy chain H4.
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pone-0022062-g005: Highest scoring Ingenuity Pathway Analysis network.Highest scoring network generated from entering the identified 29 proteins into the Ingenuity Pathway Analysis system, with proteins identified in the study shaded grey and connecting proteins identified by Ingenuity Pathway Analysis non-shaded. Dark blue shapes and lines  =  proteins identified as predictors in this study and interactions between them. Grey shapes and lines  =  proteins identified by Ingenuity to generate the network and interactions between them. Light blue lines  =  interactions between proteins identified by Ingenuity to generate the network and the proteins identified in the study. Figure S4A shows this figure with the interaction relationships labeled. Proteins identified in the study and included in the network: SERPINA1  =  alpha-1-antitrypsin; SERPINA3  =  alpha-1-antichymotrypsin; SERPINC1  =  antithrombin-III; APOA1  =  apolipoprotein A-I; APOB  =  apolipoprotein B-100; APOC3  =  apolipoprotein C-III; C3  =  complement C3; C4A, C4B  =  complement C4-A; complement C4-B; C9  =  complement component C9; GSN  =  gelsolin; HBA2  =  hemoglobin alpha; HBB, HBD  =  hemoglobin beta/delta; HP  =  haptoglobin; HPR  =  haptoglobin-related protein; HRG  =  histidine-rich glycoprotein; KLKB1  =  plasma kallikrein; IGKC  =  Ig kappa chain V-III region Ti; RBP4, Rbp  =  retinol binding protein 4; APCS  =  serum amyloid P-component; TF  =  serotransferrin; TTR  =  transthyretin. Proteins identified in the study and not included in the network: ORM1  =  alpha-1-acid glycoprotein 1; A1BG  =  alpha-1B-glycoprotein; LRG1  =  leucine-rich alpha-2-glycoprotein; ARMC2  =  armadillo repeat-containing protein 2; AHSG  =  alpha-2-HS-glycoprotein; ITIH4  =  inter-alpha-trypsin inhibitor heavy chain H4.

Mentions: Entering the 29 proteins into IPA, 5 networks were formed. The most significant network contains 24 of the 29 proteins (Figure 5). Proteins added to the network by the tool to connect the marker proteins include IL1 and NF-κB, suggesting that these proteins could also be involved in generating the observed pattern. Combining the two networks with the highest scores further adds IL1-beta, HNF1A, HNF4A, HNF6 (ONECUT1), and CEBPB as central components (Figure S4).


Proteomic biomarkers for acute interstitial lung disease in gefitinib-treated Japanese lung cancer patients.

Nyberg F, Ogiwara A, Harbron CG, Kawakami T, Nagasaka K, Takami S, Wada K, Tu HK, Otsuji M, Kyono Y, Dobashi T, Komatsu Y, Kihara M, Akimoto S, Peers IS, South MC, Higenbottam T, Fukuoka M, Nakata K, Ohe Y, Kudoh S, Clausen IG, Nishimura T, Marko-Varga G, Kato H - PLoS ONE (2011)

Highest scoring Ingenuity Pathway Analysis network.Highest scoring network generated from entering the identified 29 proteins into the Ingenuity Pathway Analysis system, with proteins identified in the study shaded grey and connecting proteins identified by Ingenuity Pathway Analysis non-shaded. Dark blue shapes and lines  =  proteins identified as predictors in this study and interactions between them. Grey shapes and lines  =  proteins identified by Ingenuity to generate the network and interactions between them. Light blue lines  =  interactions between proteins identified by Ingenuity to generate the network and the proteins identified in the study. Figure S4A shows this figure with the interaction relationships labeled. Proteins identified in the study and included in the network: SERPINA1  =  alpha-1-antitrypsin; SERPINA3  =  alpha-1-antichymotrypsin; SERPINC1  =  antithrombin-III; APOA1  =  apolipoprotein A-I; APOB  =  apolipoprotein B-100; APOC3  =  apolipoprotein C-III; C3  =  complement C3; C4A, C4B  =  complement C4-A; complement C4-B; C9  =  complement component C9; GSN  =  gelsolin; HBA2  =  hemoglobin alpha; HBB, HBD  =  hemoglobin beta/delta; HP  =  haptoglobin; HPR  =  haptoglobin-related protein; HRG  =  histidine-rich glycoprotein; KLKB1  =  plasma kallikrein; IGKC  =  Ig kappa chain V-III region Ti; RBP4, Rbp  =  retinol binding protein 4; APCS  =  serum amyloid P-component; TF  =  serotransferrin; TTR  =  transthyretin. Proteins identified in the study and not included in the network: ORM1  =  alpha-1-acid glycoprotein 1; A1BG  =  alpha-1B-glycoprotein; LRG1  =  leucine-rich alpha-2-glycoprotein; ARMC2  =  armadillo repeat-containing protein 2; AHSG  =  alpha-2-HS-glycoprotein; ITIH4  =  inter-alpha-trypsin inhibitor heavy chain H4.
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Related In: Results  -  Collection

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pone-0022062-g005: Highest scoring Ingenuity Pathway Analysis network.Highest scoring network generated from entering the identified 29 proteins into the Ingenuity Pathway Analysis system, with proteins identified in the study shaded grey and connecting proteins identified by Ingenuity Pathway Analysis non-shaded. Dark blue shapes and lines  =  proteins identified as predictors in this study and interactions between them. Grey shapes and lines  =  proteins identified by Ingenuity to generate the network and interactions between them. Light blue lines  =  interactions between proteins identified by Ingenuity to generate the network and the proteins identified in the study. Figure S4A shows this figure with the interaction relationships labeled. Proteins identified in the study and included in the network: SERPINA1  =  alpha-1-antitrypsin; SERPINA3  =  alpha-1-antichymotrypsin; SERPINC1  =  antithrombin-III; APOA1  =  apolipoprotein A-I; APOB  =  apolipoprotein B-100; APOC3  =  apolipoprotein C-III; C3  =  complement C3; C4A, C4B  =  complement C4-A; complement C4-B; C9  =  complement component C9; GSN  =  gelsolin; HBA2  =  hemoglobin alpha; HBB, HBD  =  hemoglobin beta/delta; HP  =  haptoglobin; HPR  =  haptoglobin-related protein; HRG  =  histidine-rich glycoprotein; KLKB1  =  plasma kallikrein; IGKC  =  Ig kappa chain V-III region Ti; RBP4, Rbp  =  retinol binding protein 4; APCS  =  serum amyloid P-component; TF  =  serotransferrin; TTR  =  transthyretin. Proteins identified in the study and not included in the network: ORM1  =  alpha-1-acid glycoprotein 1; A1BG  =  alpha-1B-glycoprotein; LRG1  =  leucine-rich alpha-2-glycoprotein; ARMC2  =  armadillo repeat-containing protein 2; AHSG  =  alpha-2-HS-glycoprotein; ITIH4  =  inter-alpha-trypsin inhibitor heavy chain H4.
Mentions: Entering the 29 proteins into IPA, 5 networks were formed. The most significant network contains 24 of the 29 proteins (Figure 5). Proteins added to the network by the tool to connect the marker proteins include IL1 and NF-κB, suggesting that these proteins could also be involved in generating the observed pattern. Combining the two networks with the highest scores further adds IL1-beta, HNF1A, HNF4A, HNF6 (ONECUT1), and CEBPB as central components (Figure S4).

Bottom Line: After alignment, scaling, and measurement batch adjustment, we identified 41 peptide peaks representing 29 proteins best predicting ILD.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.

View Article: PubMed Central - PubMed

Affiliation: Global Epidemiology, AstraZeneca R&D, Mölndal, Sweden. Fredrik.Nyberg@astrazeneca.com

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.

Show MeSH
Related in: MedlinePlus