title: Aberrant promoter methylation of CDH13 and MGMT genes is associated with clinicopathologic characteristics of primary non-small-cell lung carcinoma.
abstract: Non–small-cell lung carcinoma (NSCLC) (n = 65) were analyzed for promoter methylation of RASSF1A, CDH13, MGMT, ESR1, and DAPK genes in matching lung tumors, normal lung tissue, and blood samples. Aberrant methylation in CDH13 and MGMT was associated with clinicopathologic features of NSCLC. Hypermethylation detected in primary tumors was not observed in corresponding blood samples, which rendered this an unsuitable blood-based test for NSCLC detection.
  
  
  BACKGROUND
  Systemic methylation changes may be a diagnostic marker for tumor development or prognosis. Here, we investigate the relationship between gene methylation in lung tumors relative to normal lung tissue and whether DNA methylation changes can be detected in paired blood samples.
  
  
  METHODS
  Sixty-five patients were enrolled in a surgical case series of non-small-cell lung carcinoma at a single institution. By using bisulfite pyrosequencing, CpG methylation was quantified at 5 genes (RASSF1A, CDH13, MGMT, ESR1, and DAPK) in lung tumor, pathologically normal lung tissue, and circulating blood from enrolled cases.
  
  
  RESULTS
  The analyses of methylation in tumors compared with normal lung tissue identified higher methylation of CDH13, RASSF1A, and DAPK genes, whereas ESR1 and MGMT methylation did not differ significantly between these tissue types. We then examined whether the 3 aberrantly methylated genes could be detected in blood. The difference in methylation observed in tumors was not reflected in methylation status of matching blood samples, which indicated a low feasibility of detecting lung cancer by analyzing these genes in a blood-based test. Lastly, we probed whether tumor methylation was associated with clinical and demographic characteristics. Histology and sex were associated with methylation at the CDH13 gene, whereas, stage was associated with methylation at MGMT.
  
  
  CONCLUSIONS
  Our results showed higher methylation of RASSF1A, CDH13, and DAPK genes in lung tumors compared with normal lung. The lack of reflection of these methylation changes in blood samples from patients with non-small-cell lung carcinoma indicates their poor suitability for a screening test.
authors.affiliation: Pulmonology Clinic, Clinical Centre of Serbia, Medical Faculty, University in Belgrade, Belgrade, Serbia.
authors.forename: Milica
authors.initials: M
authors.lastname: Kontic
authors.forename: Jelena
authors.initials: J
authors.lastname: Stojsic
authors.forename: Dragana
authors.initials: D
authors.lastname: Jovanovic
authors.forename: Vera
authors.initials: V
authors.lastname: Bunjevacki
authors.forename: Simona
authors.initials: S
authors.lastname: Ognjanovic
authors.forename: Jacquelyn
authors.initials: J
authors.lastname: Kuriger
authors.forename: Susan
authors.initials: S
authors.lastname: Puumala
authors.forename: Heather H
authors.initials: HH
authors.lastname: Nelson
mesh_terms: D000368:Aged; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism; D015820:Cadherins / Q000235:genetics / Q000378:metabolism; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000235:genetics / Q000378:metabolism; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics* / Q000378:metabolism; D019175:DNA Methylation / Q000235:genetics*; D015254:DNA Modification Methylases / Q000235:genetics / Q000378:metabolism; D045643:DNA Repair Enzymes / Q000235:genetics / Q000378:metabolism; D064550:Death-Associated Protein Kinases; D044127:Epigenesis, Genetic; D047628:Estrogen Receptor alpha / Q000235:genetics / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D016147:Genes, Tumor Suppressor; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics* / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D011401:Promoter Regions, Genetic / Q000235:genetics; D012737:Sex Factors; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D051017:Apoptosis Regulatory Proteins; D015820:Cadherins; C506487:ESR1 protein, human; D047628:Estrogen Receptor alpha; C099972:H-cadherin; C411762:RASSF1 protein, human; D025521:Tumor Suppressor Proteins; D015254:DNA Modification Methylases; C515491:MGMT protein, human; D064550:Death-Associated Protein Kinases; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D045643:DNA Repair Enzymes