title: DNA hypermethylation analysis in sputum of asymptomatic subjects at risk for lung cancer participating in the NELSON trial: argument for maximum screening interval of 2 years.
abstract: OBJECTIVE
  Lung cancer is the major contributor to cancer mortality due to metastasised disease at time of presentation. The current study investigated DNA hypermethylation of biomarkersRASSF1A,APC, cytoglobin,3OST2, FAM19A4, PHACTR3andPRDM14in sputum of asymptomatic high-risk individuals from the NELSON lung cancer low-dose spiral CT screening trial to detect lung cancer at preclinical stage.
  
  
  METHODS
  Subjects were selected with (i) lung cancer in follow-up (cases; n=65), (ii) minor cytological aberrations (controls; n=120) and (iii) a random selection of subjects without cytological aberrations (controls; n=99). Median follow-up time for controls was 80 months. Cut-off values were based on high specificity to assess diagnostic value of the biomarkers.
  
  
  RESULTS
  RASSF1Amay denote presence of invasive cancer because of its high specificity (93% (95% CI 89% to 96%); sensitivity 17% (95% CI 4% to 31%), with best performance in a screening interval of 2 years. The panel ofRASSF1A, 3OST2andPRDM14detected 28% (95% CI 11% to 44%) of lung cancer cases within 2 years, with specificity of 90% (95% CI 86% to 94%). Sputum cytology did not detect any lung cancers.
  
  
  CONCLUSIONS
  In a lung cancer screening setting with maximum screening interval of 2 years, DNA hypermethylation analysis in sputum may play a role in the detection of preclinical disease, but complementary diagnostic markers are needed to improve sensitivity.
authors: Department of Pathology, VU University Medical Center, Amsterdam, The Netherlands.
authors: A Jasmijn
authors: AJ
authors: Hubers
authors: Department of Pathology, VU University Medical Center, Amsterdam, The Netherlands.
authors: Daniëlle A M
authors: DA
authors: Heideman
authors: Department of Pathology, VU University Medical Center, Amsterdam, The Netherlands.
authors: Sylvia
authors: S
authors: Duin
authors: Department of Epidemiology and Biostatistics, VU University Medical Center, Amsterdam, The Netherlands.
authors: Birgit I
authors: BI
authors: Witte
authors: Department of Public Health, Erasmus Medical Center, Rotterdam, The Netherlands.
authors: Harry J
authors: HJ
authors: de Koning
authors: Department of Pulmonary Diseases, University Medical Center Groningen, Groningen, The Netherlands.
authors: Harry J M
authors: HJ
authors: Groen
authors: Department of Pathology, Canisius-Wilhelmina Hospital, Nijmegen, The Netherlands.
authors: Clemens F M
authors: CF
authors: Prinsen
authors: Department of Pathology, VU University Medical Center, Amsterdam, The Netherlands.|Department of Pathology, Canisius-Wilhelmina Hospital, Nijmegen, The Netherlands.
authors: Anne S
authors: AS
authors: Bolijn
authors: Department of Pathology, Canisius-Wilhelmina Hospital, Nijmegen, The Netherlands.
authors: Mandy
authors: M
authors: Wouters
authors: Department of Pathology, Canisius-Wilhelmina Hospital, Nijmegen, The Netherlands.
authors: Susanne E
authors: SE
authors: van der Meer
authors: Department of Pathology, VU University Medical Center, Amsterdam, The Netherlands.
authors: Renske D M
authors: RD
authors: Steenbergen
authors: Department of Pathology, VU University Medical Center, Amsterdam, The Netherlands.
authors: Peter J F
authors: PJ
authors: Snijders
authors: Department of Pathology, VU University Medical Center, Amsterdam, The Netherlands.
authors: Anne
authors: A
authors: Uyterlinde
authors: Department of Epidemiology and Biostatistics, VU University Medical Center, Amsterdam, The Netherlands.
authors: Hans
authors: H
authors: Berkhof
authors: Department of Pulmonary Diseases, VU University Medical Center, Amsterdam, The Netherlands.
authors: Egbert F
authors: EF
authors: Smit
authors: Department of Pathology, VU University Medical Center, Amsterdam, The Netherlands.
authors: Erik
authors: E
authors: Thunnissen
mesh_terms: D000328:Adult; D000368:Aged; D014408:Biomarkers, Tumor / Q000032:analysis*; D019175:DNA Methylation; D055088:Early Detection of Cancer / Q000379:methods*; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000175:diagnosis*; D008297:Male; D008875:Middle Aged; D016133:Polymerase Chain Reaction; D012680:Sensitivity and Specificity; D013183:Sputum / Q000737:chemistry*; D025521:Tumor Suppressor Proteins / Q000032:analysis
chemical_list: D014408:Biomarkers, Tumor; C411762:RASSF1 protein, human; D025521:Tumor Suppressor Proteins
keywords: LUNG CANCER; ONCOGENES; PCR; SPUTUM