Aberrant promoter methylation of Caveolin-1 is associated with favorable response to taxane-platinum combination chemotherapy in advanced NSCLC

Seth A. Brodie; Courtney Lombardo; Ge Li; Jeanne Kowalski; Khanjan Gandhi; Shaojin You; Fadlo R. Khuri; Adam Marcus; Paula M. Vertino; Johann C. Brandes

doi:10.1371/journal.pone.0107124

Aberrant promoter methylation of Caveolin-1 is associated with favorable response to taxane-platinum combination chemotherapy in advanced NSCLC

Seth A. Brodie, Courtney Lombardo, Ge Li, Jeanne Kowalski, Khanjan Gandhi, Shaojin You, Fadlo R. Khuri, Adam Marcus, Paula M. Vertino, Johann C. Brandes

School of Medicine

Research output: Contribution to journal › Article › peer-review

8 Scopus citations

Abstract

Conclusions: CAV1 methylation is a predictor of disease stabilization and improved overall survival following chemotherapy with a taxane-platinum combination regimen in advanced NSCLC. CAV1 methylation may predict improved outcomes for other chemotherapeutic agents which are subject to cellular clearance mediated by caveolae.

Methods: We studied a cohort of 49 patients (median age 62 years) with advanced NSCLC treated at the Atlanta VAMC between 1999 and 2010. Methylation analysis was done on the Illumina GoldenGate Cancer panel 1 methylation microarray platform. Methylation data were correlated with clinical response and adjusted for false discovery rates.

Purpose: Aberrant promoter DNA methylation can serve as a predictive biomarker for improved clinical responses to certain chemotherapeutics. One of the major advantages of methylation biomarkers is the ease of detection and clinical application. In order to identify methylation biomarkers predictive of a response to a taxane-platinum based chemotherapy regimen in advanced NSCLC we performed an unbiased methylation analysis of 1,536 CpG dinucleotides in cancerassociated gene loci and correlated results with clinical outcomes.

Results: Cav1 methylation emerged as a powerful predictor for achieving disease stabilization following platinum taxane based chemotherapy (p = 1.21E-05, FDR significance = 0.018176). In Cox regression analysis after multivariate adjustment for age, performance status, gender, histology and the use of bevacizumab, CAV1 methylation was significantly associated with improved overall survival (HR 0.18 (95%CI: 0.03-0.94)). Silencing of CAV1 expression in lung cancer cell lines(A549, EKVX)by shRNA led to alterations in taxane retention.

Original language	English (US)
Article number	e107124
Journal	PloS one
Volume	9
Issue number	9
DOIs	https://doi.org/10.1371/journal.pone.0107124
State	Published - Sep 15 2014

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@article{bd5bd10c79154e3da0c793faa237b521,

title = "Aberrant promoter methylation of Caveolin-1 is associated with favorable response to taxane-platinum combination chemotherapy in advanced NSCLC",

abstract = "Conclusions: CAV1 methylation is a predictor of disease stabilization and improved overall survival following chemotherapy with a taxane-platinum combination regimen in advanced NSCLC. CAV1 methylation may predict improved outcomes for other chemotherapeutic agents which are subject to cellular clearance mediated by caveolae.Methods: We studied a cohort of 49 patients (median age 62 years) with advanced NSCLC treated at the Atlanta VAMC between 1999 and 2010. Methylation analysis was done on the Illumina GoldenGate Cancer panel 1 methylation microarray platform. Methylation data were correlated with clinical response and adjusted for false discovery rates.Purpose: Aberrant promoter DNA methylation can serve as a predictive biomarker for improved clinical responses to certain chemotherapeutics. One of the major advantages of methylation biomarkers is the ease of detection and clinical application. In order to identify methylation biomarkers predictive of a response to a taxane-platinum based chemotherapy regimen in advanced NSCLC we performed an unbiased methylation analysis of 1,536 CpG dinucleotides in cancerassociated gene loci and correlated results with clinical outcomes.Results: Cav1 methylation emerged as a powerful predictor for achieving disease stabilization following platinum taxane based chemotherapy (p = 1.21E-05, FDR significance = 0.018176). In Cox regression analysis after multivariate adjustment for age, performance status, gender, histology and the use of bevacizumab, CAV1 methylation was significantly associated with improved overall survival (HR 0.18 (95%CI: 0.03-0.94)). Silencing of CAV1 expression in lung cancer cell lines(A549, EKVX)by shRNA led to alterations in taxane retention.",

author = "Brodie, {Seth A.} and Courtney Lombardo and Ge Li and Jeanne Kowalski and Khanjan Gandhi and Shaojin You and Khuri, {Fadlo R.} and Adam Marcus and Vertino, {Paula M.} and Brandes, {Johann C.}",

note = "Funding Information: The authors' have read the journal's policy and the authors of this manuscript have the following competing interests: the Suntrust Scholar Award was an unconditional philanthropic gift of Suntrust Bank to the Winship Cancer Institute of Emory University to support pilot projects. The authors never had a direct connection with this commercial source. Rather, the authors' project was chosen by the Director of the Winship Cancer institute for funding based on the results of a peer review. This does not alter the authors' adherence to PLOS ONE policies on sharing data and materials. Publisher Copyright: {\textcopyright} 2014 PLOS ONE.",

year = "2014",

month = sep,

day = "15",

doi = "10.1371/journal.pone.0107124",

language = "English (US)",

volume = "9",

journal = "PloS one",

issn = "1932-6203",

publisher = "Public Library of Science",

number = "9",

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TY - JOUR

T1 - Aberrant promoter methylation of Caveolin-1 is associated with favorable response to taxane-platinum combination chemotherapy in advanced NSCLC

AU - Brodie, Seth A.

AU - Lombardo, Courtney

AU - Li, Ge

AU - Kowalski, Jeanne

AU - Gandhi, Khanjan

AU - You, Shaojin

AU - Khuri, Fadlo R.

AU - Marcus, Adam

AU - Vertino, Paula M.

AU - Brandes, Johann C.

N1 - Funding Information: The authors' have read the journal's policy and the authors of this manuscript have the following competing interests: the Suntrust Scholar Award was an unconditional philanthropic gift of Suntrust Bank to the Winship Cancer Institute of Emory University to support pilot projects. The authors never had a direct connection with this commercial source. Rather, the authors' project was chosen by the Director of the Winship Cancer institute for funding based on the results of a peer review. This does not alter the authors' adherence to PLOS ONE policies on sharing data and materials. Publisher Copyright: © 2014 PLOS ONE.

PY - 2014/9/15

Y1 - 2014/9/15

N2 - Conclusions: CAV1 methylation is a predictor of disease stabilization and improved overall survival following chemotherapy with a taxane-platinum combination regimen in advanced NSCLC. CAV1 methylation may predict improved outcomes for other chemotherapeutic agents which are subject to cellular clearance mediated by caveolae.Methods: We studied a cohort of 49 patients (median age 62 years) with advanced NSCLC treated at the Atlanta VAMC between 1999 and 2010. Methylation analysis was done on the Illumina GoldenGate Cancer panel 1 methylation microarray platform. Methylation data were correlated with clinical response and adjusted for false discovery rates.Purpose: Aberrant promoter DNA methylation can serve as a predictive biomarker for improved clinical responses to certain chemotherapeutics. One of the major advantages of methylation biomarkers is the ease of detection and clinical application. In order to identify methylation biomarkers predictive of a response to a taxane-platinum based chemotherapy regimen in advanced NSCLC we performed an unbiased methylation analysis of 1,536 CpG dinucleotides in cancerassociated gene loci and correlated results with clinical outcomes.Results: Cav1 methylation emerged as a powerful predictor for achieving disease stabilization following platinum taxane based chemotherapy (p = 1.21E-05, FDR significance = 0.018176). In Cox regression analysis after multivariate adjustment for age, performance status, gender, histology and the use of bevacizumab, CAV1 methylation was significantly associated with improved overall survival (HR 0.18 (95%CI: 0.03-0.94)). Silencing of CAV1 expression in lung cancer cell lines(A549, EKVX)by shRNA led to alterations in taxane retention.

AB - Conclusions: CAV1 methylation is a predictor of disease stabilization and improved overall survival following chemotherapy with a taxane-platinum combination regimen in advanced NSCLC. CAV1 methylation may predict improved outcomes for other chemotherapeutic agents which are subject to cellular clearance mediated by caveolae.Methods: We studied a cohort of 49 patients (median age 62 years) with advanced NSCLC treated at the Atlanta VAMC between 1999 and 2010. Methylation analysis was done on the Illumina GoldenGate Cancer panel 1 methylation microarray platform. Methylation data were correlated with clinical response and adjusted for false discovery rates.Purpose: Aberrant promoter DNA methylation can serve as a predictive biomarker for improved clinical responses to certain chemotherapeutics. One of the major advantages of methylation biomarkers is the ease of detection and clinical application. In order to identify methylation biomarkers predictive of a response to a taxane-platinum based chemotherapy regimen in advanced NSCLC we performed an unbiased methylation analysis of 1,536 CpG dinucleotides in cancerassociated gene loci and correlated results with clinical outcomes.Results: Cav1 methylation emerged as a powerful predictor for achieving disease stabilization following platinum taxane based chemotherapy (p = 1.21E-05, FDR significance = 0.018176). In Cox regression analysis after multivariate adjustment for age, performance status, gender, histology and the use of bevacizumab, CAV1 methylation was significantly associated with improved overall survival (HR 0.18 (95%CI: 0.03-0.94)). Silencing of CAV1 expression in lung cancer cell lines(A549, EKVX)by shRNA led to alterations in taxane retention.

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DO - 10.1371/journal.pone.0107124

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JO - PloS one

JF - PloS one

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Aberrant promoter methylation of Caveolin-1 is associated with favorable response to taxane-platinum combination chemotherapy in advanced NSCLC

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