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Original Research: CANCER |

Diagnosing Peripheral Lung CancerBiomarkers Guide Diagnosis in Bronchial Washings: The Additional Value of the Ras-Association Domain Family 1A Gene Methylation and Kirsten Rat Sarcoma 2 Viral Oncogene Homolog Mutation Analyses in Washings in Nondiagnostic Bronchoscopy

Miep A. van der Drift, MD; Clemens F. M. Prinsen, PhD; G. Jimmy Knuiman, MD; Julius P. Janssen, MD, PhD, FCCP; P. N. Richard Dekhuijzen, MD, PhD; Frederic B. J. M. Thunnissen, MD, PhD
Author and Funding Information

From the Department of Pulmonary Diseases (Drs van der Drift and Dekhuijzen), Radboud University Nijmegen Medical Centre, Nijmegen; and the Departments of Pathology (Drs Prinsen, Knuiman, and Thunnissen) and of Pulmonary Diseases (Dr Janssen), Canisius-Wilhelmina Hospital, Nijmegen, The Netherlands.

Correspondence to: Miep A. van der Drift, MD, Department of Pulmonology, Dekkerswald, Radboud University Nijmegen Medical Centre, Postbus 66, 6560 AB, Groesbeek, The Netherlands; e-mail: m.vanderdrift@uccz.umcn.nl


Dr Thunnissen is currently at the Department of Pathology, Free University Medical Centre (VU) (Amsterdam, The Netherlands).

Parts of this study were presented and published in abstract form at the World Conference of Lung Cancer, Barcelona, Spain, 2005 (Lung Cancer. 2005;49:S2970), and San Francisco, California, 2009 (J Thorac Oncol. 2009;4(9):S472).

Funding/Support: The authors have reported to CHEST that no funding was received for this study.

Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (http://www.chestpubs.org/site/misc/reprints.xhtml).


© 2012 American College of Chest Physicians


Chest. 2012;141(1):169-175. doi:10.1378/chest.10-2579
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Background:  The diagnostic yield of bronchoscopy in patients with endoscopically nonvisible (peripheral) tumors varies from 40% to 56%. Increasingly, molecular markers in bronchial washings are being investigated to improve the diagnostic yield. The aim of this study was to analyze the diagnostic value of the Ras association domain family 1A gene (RASSF1A) methylation analysis in washings in nondiagnostic bronchoscopy in the analysis of patients with suspected lung cancer who had peripheral tumors. Furthermore, the additional diagnostic value of Kirsten rat sarcoma 2 viral oncogene homolog (KRAS) mutations with RASSF1 methylation was analyzed.

Methods:  From a prospectively collected series, 129 patients with lung cancer and 28 control subjects were analyzed retrospectively regarding the methylation status of the promoter region of the RASSF1A gene by quantitative methylation-specific polymerase chain reaction and KRAS point mutations by using the sensitive Point-EXACCT method.

Results:  A total of 40% of the lung cancer patients had peripheral tumors, and 17 patients had a nondiagnostic bronchoscopy. In these patients, RASSF1A methylation was detected in the washings of four patients (24%), and KRAS mutations were detected in the washings of two patients (12%). In total, 29% of the false-negative or doubtful cytology results were accompanied by RASSF1A methylation or KRAS mutation results that were highly suggestive of malignancy. The proportion of RASSF1A methylation was significantly higher in central and larger tumors. No relevant RASSF1A methylation was detected in control samples.

Conclusions:  Our data suggest that the molecular analysis of two biomarkers in nondiagnostic bronchial washings may better guide diagnostic procedures in patients with suspected lung cancer.


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