A Jasmijn Hubers1, Miep A van der Drift2, Clemens F M Prinsen3, Birgit I Witte4, Yinghui Wang5, Narayan Shivapurkar6, Victor Stastny6, Anne S Bolijn3, Bernard E A Hol7, Ziding Feng5, P N Richard Dekhuijzen2, Adi F Gazdar6, Erik Thunnissen8. 1. Department of Pathology, VU University Medical Center, Amsterdam, The Netherlands. 2. Department of Pulmonology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands. 3. Department of Pathology, Canisius-Wilhelmina Hospital, Nijmegen, The Netherlands. 4. Department of Epidemiology and Biostatistics, VU University Medical Center, Amsterdam, The Netherlands. 5. Fred Hutchinson Cancer Research Center, Seattle, USA. 6. Hamon Center for Therapeutic Oncology Research, UT Southwestern Medical Center, Dallas, USA. 7. Department of Pulmonology, Canisius Wilhelmina Hospital, Nijmegen, The Netherlands. 8. Department of Pathology, Canisius-Wilhelmina Hospital, Nijmegen, The Netherlands. Electronic address: e.thunnissen@vumc.nl.
Abstract
OBJECTIVES: Lung cancer is the most fatal cancer in the developed world due to presence of metastases at time of diagnosis. The aim of this study is to examine DNA hypermethylation in sputum compared to sputum cytology for the diagnosis of lung cancer. A novel risk analysis is introduced, using the distinction between diagnostic and risk markers. METHODS: Two independent sets were randomly composed from a prospectively collected sputum bank (Set 1: n = 98 lung cancer patients, n = 90 controls; Set 2: n = 60 lung cancer patients, n = 445 controls). Sputum cytology was performed for all samples. The following DNA hypermethylation markers were tested in both sets: RASSF1A, APC and cytoglobin (CYGB). Two statistical analyses were conducted: multivariate logistic regression and a risk classification model based on post-test probabilities. RESULTS: In multivariate analysis, RASSF1A was the best of the three markers in discriminating lung cancer cases from controls in both sets (sensitivity 41-52%, specificity 94-96%). The risk model showed that 36% of lung cancer patients were defined as "high risk" (≥ 60% chance on lung cancer) based on RASSF1A hypermethylation in Set 1. The model was reproducible in Set 2. Risk markers (APC, CYGB) have less diagnostic value. Sensitivity of cytology for lung cancer diagnosis was 22%. RASSF1A hypermethylation yielded a sensitivity of 45%. The combined sensitivity for RASSF1A with cytological diagnosis increased to 52% with similar specificity (94%). CONCLUSION: In a diagnostic setting, hypermethylation analysis in sputum is possible when a diagnostic marker is used. However, risk markers are insufficient for this purpose.
OBJECTIVES:Lung cancer is the most fatal cancer in the developed world due to presence of metastases at time of diagnosis. The aim of this study is to examine DNA hypermethylation in sputum compared to sputum cytology for the diagnosis of lung cancer. A novel risk analysis is introduced, using the distinction between diagnostic and risk markers. METHODS: Two independent sets were randomly composed from a prospectively collected sputum bank (Set 1: n = 98 lung cancerpatients, n = 90 controls; Set 2: n = 60 lung cancerpatients, n = 445 controls). Sputum cytology was performed for all samples. The following DNA hypermethylation markers were tested in both sets: RASSF1A, APC and cytoglobin (CYGB). Two statistical analyses were conducted: multivariate logistic regression and a risk classification model based on post-test probabilities. RESULTS: In multivariate analysis, RASSF1A was the best of the three markers in discriminating lung cancer cases from controls in both sets (sensitivity 41-52%, specificity 94-96%). The risk model showed that 36% of lung cancerpatients were defined as "high risk" (≥ 60% chance on lung cancer) based on RASSF1A hypermethylation in Set 1. The model was reproducible in Set 2. Risk markers (APC, CYGB) have less diagnostic value. Sensitivity of cytology for lung cancer diagnosis was 22%. RASSF1A hypermethylation yielded a sensitivity of 45%. The combined sensitivity for RASSF1A with cytological diagnosis increased to 52% with similar specificity (94%). CONCLUSION: In a diagnostic setting, hypermethylation analysis in sputum is possible when a diagnostic marker is used. However, risk markers are insufficient for this purpose.
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