title: Defining a gene promoter methylation signature in sputum for lung cancer risk assessment.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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 highest risk smokers for computed tomographic screening for early detection of lung cancer.
authors.affiliation: Lung Cancer Program, Lovelace Respiratory Research Institute, Department of Internal Medicine, University of New Mexico, Albuquerque, New Mexico 87108, USA.
authors.forename: Shuguang
authors.initials: S
authors.lastname: Leng
authors.forename: Kieu
authors.initials: K
authors.lastname: Do
authors.forename: Christin M
authors.initials: CM
authors.lastname: Yingling
authors.forename: Maria A
authors.initials: MA
authors.lastname: Picchi
authors.forename: Holly J
authors.initials: HJ
authors.lastname: Wolf
authors.forename: Timothy C
authors.initials: TC
authors.lastname: Kennedy
authors.forename: William J
authors.initials: WJ
authors.lastname: Feser
authors.forename: Anna E
authors.initials: AE
authors.lastname: Baron
authors.forename: Wilbur A
authors.initials: WA
authors.lastname: Franklin
authors.forename: Malcolm V
authors.initials: MV
authors.lastname: Brock
authors.forename: James G
authors.initials: JG
authors.lastname: Herman
authors.forename: Stephen B
authors.initials: SB
authors.lastname: Baylin
authors.forename: Tim
authors.initials: T
authors.lastname: Byers
authors.forename: Christine A
authors.initials: CA
authors.lastname: Stidley
authors.forename: Steven A
authors.initials: SA
authors.lastname: Belinsky
mesh_terms: D000368:Aged; D014408:Biomarkers, Tumor / Q000235:genetics*; D016022:Case-Control Studies; D015331:Cohort Studies; D019175:DNA Methylation; D005260:Female; D055106:Genome-Wide Association Study; D006801:Humans; D008175:Lung Neoplasms / Q000175:diagnosis / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic; D018570:Risk Assessment; D013183:Sputum / Q000166:cytology*
chemical_list: D014408:Biomarkers, Tumor