Defining a Gene Promoter Methylation Signature in Sputum for Lung Cancer Risk Assessment

作者：Shuguang Leng, Kieu Do, Christin M. Yingling, Maria A. Picchi, Holly J. Wolf, Timothy C. Kennedy, William J. Feser, Anna E. Barón, Wilbur A. Franklin, Malcolm V. Brock, James Gordon Herman, Stephen B. Baylin, Tim Byers, Christine A. Stidley, Steven A. Belinsky · 发表于：Clinical Cancer Research · 年份：2012 · DOI：10.1158/1078-0432.ccr-11-3049 · 被引用次数：101 · 研究领域：Lung Cancer Treatments and Mutations、Epigenetics and DNA Methylation、Lung Cancer Diagnosis and Treatment

PURPOSE: To evaluate the methylation state of 31 genes in sputum as biomarkers in an expanded nested, case-control study from the Colorado cohort, and to assess the replication of results from the most promising genes in an independent case-control study of asymptomatic patients with stage I lung cancer from New Mexico. EXPERIMENTAL DESIGN: Cases and controls from Colorado and New Mexico were interrogated for methylation of up to 31 genes using nested, methylation-specific PCR. Individual genes and methylation indices were used to assess the association between methylation and lung cancer with logistic regression modeling. RESULTS: Seventeen genes with ORs of 1.4 to 3.6 were identified and selected for replication in the New Mexico study. Overall, the direction of effects seen in New Mexico was similar to Colorado with the largest increase in case discrimination (ORs, 3.2-4.2) seen for the PAX5α, GATA5, and SULF2 genes. Receiver operating characteristic (ROC) curves generated from seven-gene panels from Colorado and New Mexico studies showed prediction accuracy of 71% and 77%, respectively. A 22-fold increase in lung cancer risk was seen for a subset of New Mexico cases with five or more genes methylated. Sequence variants associated with lung cancer did not improve the accuracy of this gene methylation panel. CONCLUSIONS: These studies have identified and replicated a panel of methylated genes whose integration with other promising biomarkers could initially identify the hig...