DNA Methylation Biomarkers Offer Improved Diagnostic Efficiency in Lung Cancer
- 14 November 2012
- journal article
- research article
- Published by American Association for Cancer Research (AACR) in Cancer Research
- Vol. 72 (22), 5692-5701
- https://doi.org/10.1158/0008-5472.can-12-2309
Abstract
The exceptional high mortality of lung cancer can be instigated to a high degree by late diagnosis. Despite the plethora of studies on potential molecular biomarkers for lung cancer diagnosis, very few have reached clinical implementation. In this study, we developed a panel of DNA methylation biomarkers and validated their diagnostic efficiency in bronchial washings from a large retrospective cohort. Candidate targets from previous high-throughput approaches were examined by pyrosequencing in an independent set of 48 lung tumor/normal paired. Ten promoters were selected and quantitative methylation-specific PCR (qMSP) assays were developed and used to screen 655 bronchial washings from the Liverpool Lung Project (LLP) subjects divided into training (194 cases and 214 controls) and validation (139 cases and 109 controls) sets. Three statistical models were used to select the optimal panel of markers and to evaluate the performance of the discriminatory algorithms. The final logit regression model incorporated hypermethylation at p16, TERT, WT1, and RASSF1. The performance of this 4-gene methylation signature in the validation set showed 82% sensitivity and 91% specificity. In comparison, cytology alone in this set provided 43% sensitivity at 100% specificity. The diagnostic efficiency of the panel did not show any biases with age, gender, smoking, and the presence of a nonlung neoplasm. However, sensitivity was predictably higher in central (squamous and small cell) than peripheral (adenocarcinomas) tumors, as well as in stage 2 or greater tumors. These findings clearly show the impact of DNA methylation-based assays in the diagnosis of cytologically occult lung neoplasms. A prospective trial is currently imminent in the LLP study to provide data on the enhancement of diagnostic accuracy in a clinical setting, including by additional markers. Cancer Res; 72(22); 5692–701. ©2012 AACR.Other Versions
This publication has 49 references indexed in Scilit:
- Performance evaluation of the DNA methylation biomarker SHOX2 for the aid in diagnosis of lung cancer based on the analysis of bronchial aspiratesInternational Journal of Oncology, 2011
- Lung cancer incidence and survival in different ethnic groups in South East EnglandBritish Journal of Cancer, 2011
- Reduced Lung-Cancer Mortality with Low-Dose Computed Tomographic ScreeningThe New England Journal of Medicine, 2011
- Correlation of SHOX2 Gene Amplification and DNA Methylation in Lung Cancer TumorsBMC Cancer, 2011
- UK Lung Screen (UKLS) nodule management protocol: modelling of a single screen randomised controlled trial of low-dose CT screening for lung cancerThorax, 2011
- Screening and Early Detection of Lung CancerThe Cancer Journal, 2011
- SHOX2 DNA Methylation is a Biomarker for the diagnosis of lung cancer based on bronchial aspiratesBMC Cancer, 2010
- Multiple genetic and epigenetic biomarkers for lung cancer detection in cytologically negative sputum and a nested case–control study for risk assessmentThe Journal of Pathology, 2007
- Application of a methylation gene panel by quantitative PCR for lung cancersCancer Letters, 2007
- Promoter methylation of genes in bronchial lavages: A marker for early diagnosis of primary and relapsing non-small cell lung cancer?Lung Cancer, 2005