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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

Significant associated pathways with ILD status.The most significant pathways from an analysis linking the identified 29 proteins from the study to curated pathways in the Ingenuity Pathway Analysis system are shown, ordered according to the ratio between the number of protein markers that can be associated with the pathway and the number of proteins in the pathway.
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pone-0022062-g004: Significant associated pathways with ILD status.The most significant pathways from an analysis linking the identified 29 proteins from the study to curated pathways in the Ingenuity Pathway Analysis system are shown, ordered according to the ratio between the number of protein markers that can be associated with the pathway and the number of proteins in the pathway.

Mentions: This set of proteins was then used in the biological interpretation analyses, using the Ingenuity Pathway Analysis (IPA) system. The most significant pathway found when overlaying the proteins onto Ingenuity-curated canonical pathways was the acute phase response signaling pathway, with which 17 of the 29 proteins could be associated (p = 1.0×10−25). Other pathways showing a high overlap with the list of proteins included the complement and coagulation pathways, but p-values were less significant due to the smaller number of proteins involved (Figure 4).


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)

Significant associated pathways with ILD status.The most significant pathways from an analysis linking the identified 29 proteins from the study to curated pathways in the Ingenuity Pathway Analysis system are shown, ordered according to the ratio between the number of protein markers that can be associated with the pathway and the number of proteins in the pathway.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3140475&req=5

pone-0022062-g004: Significant associated pathways with ILD status.The most significant pathways from an analysis linking the identified 29 proteins from the study to curated pathways in the Ingenuity Pathway Analysis system are shown, ordered according to the ratio between the number of protein markers that can be associated with the pathway and the number of proteins in the pathway.
Mentions: This set of proteins was then used in the biological interpretation analyses, using the Ingenuity Pathway Analysis (IPA) system. The most significant pathway found when overlaying the proteins onto Ingenuity-curated canonical pathways was the acute phase response signaling pathway, with which 17 of the 29 proteins could be associated (p = 1.0×10−25). Other pathways showing a high overlap with the list of proteins included the complement and coagulation pathways, but p-values were less significant due to the smaller number of proteins involved (Figure 4).

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